Aliphatic nitrogen-containing 5-membered ring compound

ABSTRACT

The present invention is to provide an aliphatic nitrogen-containing 5-membered ring compound represented by the formula [I]: 
     
       
         
         
             
             
         
       
         
         
           
             wherein A represents —CH 2 — or —S—, 
             R 1  represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower-alkoxy lower alkyl group, 
             X represents —N(R 3 )—, —O— or —CO—, where R 3  represents hydrogen atom or a lower alkyl group, and 
             R 2  represents (1) a cyclic group which may be substituted, or (2) an amino group which may be substituted,
 
or a pharmaceutically acceptable salt thereof, a method for preparing the above-mentioned compound and a pharmaceutical composition comprising the above-mentioned compound as an effective ingredient.

This application is a divisional of U.S. patent application Ser. No.10/398,486, filed Apr. 4, 2003, now U.S. Pat. No. 6,849,622 which wasfiled under 35 U.S.C. 371 and is based on International ApplicationPCT/JP01/08803, filed Oct. 5, 2001, both of which are hereinincorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel aliphatic nitrogen-containing5-membered ring compound having superior dipeptidylpeptidase IV (DPPIV)inhibitory action that is useful as a pharmaceutical.

BACKGROUND ART

Dipeptidylpeptidase IV (DPPIV) is a kind of serine protease thatspecifically hydrolyzes a dipeptide of Xaa-Pro or Xaa-Ala (where Xaa maybe any amino acid) from the N terminus of a polypeptide chain.

There are various reports regarding the role of DPPIV (also called to asCD26) in the body and its relationship with diseases (Holst, et al.,Diabetes, Vol. 47, pp. 1663–1670, 1998; Augustyns, et al., CurrentMedicinal Chemistry, Vol. 6, pp. 311–327, 1999; Meester, et al.,Immunol. Today, Vol. 20, pp. 367–375, 1999; and, Fleicher, et al.,Immunol. Today, Vol. 15, pp. 180–184, 1994).

GLP-1 (glucagon-like peptide 1) is a peptide hormone that mainly acts inthe pancreas after being secreted from the lower small intestine aftermeals, and primarily has the function of amplifying glucose-inducedinsulin secretion. In addition, there are several reports suggestingthat GLP-1 has an appetite-suppressing action. DPPIV hydrolyzes GLP-1,forming an inactive or antagonistic peptide.

Substances that inhibit the enzyme activity of DPPIV enhance the insulinsecretion response to oral glucose loading by enhancing the action ofintrinsic GLP-1, thereby improving impaired glucose tolerance.

Consequently, DPPIV inhibitors are considered to be useful for theprophylaxis and treatment of diabetes (particularly type 2 diabetes),etc. Also, they are expected to be effective for the prophylaxis andtreatment of other diseases induced or exacerbated by impaired glucosetolerance (including hyperglycemia (such as postprandial hyperglycemia),hyperinsulinemia, diabetes complications (such as renal disorder andneurological disorder), lipid metabolism disorder and obesity, etc.).

Moreover, DPPIV inhibitors are also expected to be effective for theprophylaxis and treatment of diseases that are to be improved byenhancing the appetite-suppressing action of GLP-1 (including overeatingand obesity, etc.).

Also, DPPIV (CD26) present on the surface of T cells is stronglyupregulated following T cell activation, and plays an important role inthe activation and proliferation of T cells. T cell activity is known tobe suppressed when DPPIV (CD26) is blocked by antibodies or inhibitorysubstances. Also, there has been an interest in the correlation betweenthis enzyme and the pathological state in collagen metabolism disordersand diseases associated with abnormal immunity. For example, the DPPIV(CD26) positive rate of peripheral blood T cells is elevated inrheumatoid patients, and high levels of DPPIV activity have beendetected in the urine of nephritis patients. Moreover, DPPIV (CD26) isalso thought to play an important role in the entry of HIV intolymphocytes.

Consequently, substances that inhibit DPPIV (CD26) are expected todemonstrate prophylactic and therapeutic effects against diseasesincluding autoimmune diseases (such as arthritis and rheumatoidarthritis), osteoporosis, acquired immunodeficiency syndrome (AIDS) andrejections of transplanted organs and tissues.

On the other hand, as compounds having DPPIV inhibitory action, thereare described 2-cyanopyrrolidine derivatives having DPPIV inhibitoryaction in International Patent Laid-Open Publications Nos. WO98/19998and

The present invention provides a novel aliphatic nitrogen-containing5-membered ring compound having an excellent DPPIV inhibitory action.

DISCLOSURE OF THE INVENTION

As a result of earnest research to solve the above problems, the presentinventors found a novel aliphatic nitrogen-containing 5-membered ringcompound having DPPIV inhibitory action, thereby accomplished thepresent invention.

Namely, the present invention relates to an aliphaticnitrogen-containing 5-membered ring compound represented by the formula[I]:

-   -   wherein A represents —CH₂— or —S—,    -   R¹ represents hydrogen atom, a lower alkyl group, a hydroxy        lower alkyl group or a lower alkoxy lower alkyl group,    -   X represents —N(R³)—, —O— or —CO—, where R³ represents hydrogen        atom or a lower alkyl group, and    -   R² represents (1) a cyclic group which may be substituted, where        the cyclic group portion is    -   (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or    -   (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or    -   (2) an amino group which may be substituted,        or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

Although optical isomers based on an asymmetric carbon can be present inthe objective compound [I] of the present invention, the presentinvention includes any of these optical isomers as well as mixturesthereof. In addition, although isomers (cis form or trans form) are alsopresent based on the relative positions of substituents with respect tothe standard plane of a cyclic group, the present invention alsoincludes any of these isomers as well as mixtures thereof.

In the present invention, examples of a lower alkyl group, a loweralkylthio group, a lower alkylsulfonyl group, a lower alkoxy group and alower alkylamino group include linear or branched groups having 1 to 6carbon atoms, and particularly those having 1 to 4 carbon atoms. And,examples of a lower alkanoyl group and a lower alkanoylamino groupinclude linear or branched groups having 2 to 7 carbon atoms, andparticularly those having 2 to 5 carbon atoms. Examples of a lowercycloalkyl group and lower cycloalkenyl group include those having 3 to8 carbon atoms, and particularly 3 to 6 carbon atoms. Examples of alower alkylene group include linear or branched groups having 1 to 6carbon atoms, and particularly 1 to 4 carbon atoms. Examples of a loweralkenyl group and lower alkenylene group include those having 2 to 7carbon atoms, and particularly 2 to 5 carbon atoms. Further, examples ofa halogen atom include fluorine, chlorine, bromine and iodine.

In the objective compound [I] of the present invention, examples ofhydrogen atom or a lower alkyl group represented by R³ include hydrogenatom, methyl group, etc. Among them, hydrogen atom is more preferred.

In the compound [I] of the present invention, examples of “hydrogenatom, a lower alkyl group, a hydroxy lower alkyl group or lower alkoxylower alkyl group” represented by R¹ include hydrogen atom, methylgroup, hydroxymethyl group and methoxymethyl group. Among them, hydrogenatom is preferred.

In the compound [I] of the present invention, a cyclic group portion of“a cyclic group which may be substituted” represented by R² includes

-   (i) a monocyclic, bicyclic or tricyclic hydrocarbon group and-   (ii) a monocyclic, bicyclic or tricyclic heterocyclic group.

Such monocyclic, bicyclic or tricyclic hydrocarbon groups include thosehaving 3 to 15 carbon atoms, which may be partially or completelysaturated.

Monocyclic hydrocarbon groups include those having 3 to 7 carbon atoms,examples of which include phenyl group, cyclohexyl group, cyclopentylgroup, cyclobutyl group, cyclopropyl group, etc.

Bicyclic hydrocarbon groups include those having 9 to 11 carbon atoms,examples of which include an indanyl group, an indenyl group, a naphthylgroup, a tetrahydronaphthyl group and partially or completely saturatedcyclic groups thereof, etc.

Tricyclic hydrocarbon groups include those having 12 to 15 carbon atoms,examples of which include a fluorenyl group, an anthryl group, aphenanthryl group and partially or completely saturated cyclic groupsthereof, etc.

Monocyclic, bicyclic or tricyclic heterocyclic groups include amonocyclic, bicyclic or tricyclic heterocyclic group containing 1 to 4hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,which may be partially or completely saturated.

Monocyclic heterocyclic groups include a heterocyclic group containing 1or 2 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom and comprising of a saturated or unsaturated 5- to 7-membered ring,examples of which include: pyrrolidinyl group, an imidazolidinyl group,a pyrazolidinyl group, an oxolanyl group, a thiolanyl group, apyrrolinyl group, an imidazolinyl group, a pyrazolinyl group, a pyrrolylgroup, an imidazolyl group, a pyrazolyl group, a triazolyl group, atetrazolyl group, a furyl group, an oxazolyl group, an isoxazolyl group,an oxadiazolyl group, a thienyl group, a thiazolyl group, anisothiazolyl group, a thiadiazolyl group, a piperidyl group, apiperazinyl group, a morpholinyl group, a thiomorpholinyl group, apyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinylgroup, a pyranyl group, a tetrahydropyridyl group, a dihydropyridazinylgroup, a perhydroazepinyl group, a perhydrothiazepinyl and partially orcompletely saturated cyclic groups thereof, etc.

Bicyclic heterocyclic groups include a heterocyclic group containing 1to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom and comprising two saturated or unsaturated 5- to 7-membered ringsbeing fused, examples of which include:

-   an indolinyl group, an isoindolinyl group, an indolyl group, an    indazolyl group, an isoindolyl group, a benzimidazolyl group, a    benzothiazolyl group, a benzoxazolyl group, a benzodioxolanyl group,    a benzothienyl group, a benzofuryl group, a thienopyridyl group, a    thiazolopyridyl group, a pyrrolopyridyl group, a    dihydropyrrolopyridyl group, a quinolyl group, an isoquinolyl group,    a quinoxalinyl group, a quinazolinyl group, a phthalazinyl group, a    cinnolinyl group, a chromanyl group, an isochromanyl group, a    naphthyridinyl group and partially or completely saturated cyclic    groups thereof, etc.

Tricyclic heterocyclic groups include a heterocyclic group containing 1to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfuratom and comprising three saturated or unsaturated 5- to 7-memberedrings being fused, examples of which include:

-   a benzoxolanopyrimidyl group, a β-carbolinyl group, a carbazolyl    group, a phenothiazinyl group, a phenoxazinyl group and partially or    completely saturated cyclic groups thereof, etc.

Among these cyclic groups (monocyclic, bicyclic or tricyclic hydrocarbongroups or monocyclic, bicyclic or tricyclic heterocyclic groups),

-   “(i) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,-   (ii) a bicyclic hydrocarbon groups having 9 to 11 carbon atoms,-   (iii) a monocyclic heterocyclic group containing 1 or 2 hetero atoms    selected from nitrogen atom, oxygen atom and sulfur atom, or-   (iv) a bicyclic heterocyclic group containing 1 to 3 hetero atoms    selected from nitrogen atom, oxygen atom and sulfur atom and    comprising two 5- to 7-membered rings being fused” is preferred,    examples of which include:-   “phenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl    group, cyclopropyl group, an indanyl group, an indenyl group, a    naphthyl group, tetrahydronaphthyl, a pyrrolidinyl group, an    imidazolidinyl group, a pyrazolidinyl group, an oxolanyl group, a    thiolanyl group, a pyrrolinyl group, an imidazolinyl group, a    pyrazolinyl group, a pyrrolyl group, an imidazolyl group, a    pyrazolyl group, a triazolyl group, a tetrazolyl group, a furyl    group, an oxazolyl group, an isoxazolyl group, an oxadiazolyl group,    a thienyl group, a thiazolyl group, an isothiazolyl group, a    thiadiazolyl group, a piperidyl group, a piperazinyl group, a    morpholinyl group, a thiomorpholinyl group, a pyridyl group, a    pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a pyranyl    group, a tetrahydropyridyl group, a dihydropyridazinyl group, a    perhydroazepinyl group, a perhydrothiazepinyl group, an indolinyl    group, an isoindolinyl group, an indolyl group, an indazolyl group,    an isoindolyl group, a benzimidazolyl group, a benzothiazolyl group,    a benzoxazolyl group, a benzodioxolanyl group, a benzothienyl group,    a benzofuryl group, a thienopyridyl group, a thiazolopyridyl group,    a pyrrolopyridyl group, a dihydropyrrolopyridyl group, a quinolyl    group, an isoquinolyl group, a quinoxalinyl group, a quinazolinyl    group, a phthalazinyl group, a cinnolinyl group, a chromanyl group,    an isochromanyl group, a naphthyridinyl group and partially or    completely saturated cyclic groups thereof, etc.”.

Among them, more preferred examples include:

-   “phenyl group, cyclohexyl group, a pyrrolidinyl group, a tetrazolyl    group, a furyl group, a thienyl group, a thiazolyl group, a    piperidyl group, a piperazinyl group, a morpholinyl group, a    thiomorpholinyl group, a pyridyl group, a pyrimidinyl group, a    pyrazinyl group, a pyridazinyl group, a perhydroazepinyl group, an    indolinyl group, an isoindolinyl group, a benzothienyl group, a    thienopyridyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl    group, a quinolyl group, an isoquinolyl group, a quinoxalinyl group    and partially or completely saturated cyclic groups thereof, etc.”,    and further preferred examples include:-   “a pyrrolidinyl group, a piperidyl group, a piperazinyl group, a    morpholinyl group, a thiomorpholinyl group, a pyridyl group, a    pyrimidinyl group, an indolinyl group, an isoindolinyl group, a    pyrrolopyridyl group, a dihydropyrrolopyridyl group and partially or    completely saturated cyclic groups thereof, etc.”

Among them, particularly preferred examples include: “1-pyrrolidinylgroup, 1-piperidyl group, 1-piperazinyl group, 4-morpholinyl group,4-thiomorpholinyl group, 2-pyridyl group, 2-pyrimidinyl group,2-isoindolinyl group, 1-indolinyl group,2,3-dihydro-1H-pyrrolo[3,4-b]pyridin-2-yl group, etc.”.

“A cyclic group (a monocyclic, bicyclic or tricyclic hydrocarbon groupor a monocyclic, bicyclic or tricyclic heterocyclic group) which may besubstituted” represented by R² may be unsubstituted or have 1 to 3substituents which-are the same or different.

Substituents in the cyclic group are not particularly limited, andexamples of which include substituents selected from the following“substituents of Group A”. Among them, “substituents of Group A′” aremore preferred.

In the objective compound [I] of the present invention, “an amino groupwhich may be substituted” represented by R² may be unsubstituted or maybe an amino group having 1 or 2 substituents which are the same ordifferent (a mono- or di-substituted amino group).

Substituents in the amino group are not particularly limited, andexamples of which include substituents selected from the following“substituents of Group B”. Among them, “substituents of Group B′” aremore preferred.

“An amino group which may be substituted” represented by R² ispreferably a substituted amino group (a mono- or di-substituted aminogroup), and more specifically “an amino group substituted by 1 or 2substituents which are the same or different and selected from the groupconsisting of a lower alkyl group (methyl group, ethyl group, isopropylgroup, butyl group, etc.), a lower cycloalkyl group, a loweralkoxy-substituted lower alkyl group, a pyrimidinyl group, a thiazolylgroup and a thiadiazolyl group” is preferred. Among them,

-   “(i) an amino group di-substituted by substituents which are the    same or different and selected from a lower alkyl group (methyl    group, ethyl group, isopropyl group, butyl group, etc.), a lower    cycloalkyl group and a lower alkoxy-substituted lower alkyl group;    or-   (ii) an amino group mono-substituted by a substituent selected from    a pyrimidinyl group, a thiazolyl group and a thiadiazolyl group” is    more preferred, and “an amino group di-substituted by substituents    which are the same or different and selected from a lower alkyl    group (methyl group, ethyl group, isopropyl group, butyl group,    etc.), a lower cycloalkyl group and a lower alkoxy-substituted lower    alkyl group” is particularly preferred.

Substituents of Group A

As substituents of Group A, the following substituents are mentioned:

-   a halogen atom (Cl, F, Br, etc.); cyano group; nitro group, oxo    group, hydroxy group, carboxy group; oxidyl group; amino group;    carbamoyl group; aminosulfonyl group; a lower alkyl group; a lower    alkoxy group; a lower alkanoyl group; a lower alkoxycarbonyl group;    a lower alkoxy-substituted lower alkanoyl group; a lower    alkoxycarbonyl-substituted lower alkoxy group; a lower    alkoxycarbonyl-substituted lower alkoxycarbonyl group;-   a lower alkylthio group;-   a lower alkylsulfonyl group;-   a di-lower alkylamino-substituted lower alkoxy group;-   a di-lower alkylaminocarboxy group;-   a lower alkyl group substituted by group(s) selected from amino    group, carbamoyl group, a halogen atom, hydroxy group, carboxy    group, a lower alkoxy group and a mono- or di-substituted amino    group-   (substituents in the substituted amino group portion are not    particularly limited, and examples of which include substituents of    Group C mentioned below.);-   a mono- or di-substituted amino group or a mono- or di-substituted    carbamoyl group-   (substituents in the substituted amino group or substituted    carbamoyl group are not particularly limited, and examples of which    include substituents of Group C mentioned below.);-   a substituted or unsubstituted lower cycloalkyl group,-   a substituted or unsubstituted lower cycloalkyl-CO—,-   a substituted or unsubstituted lower cycloalkyl-lower alkyl group,-   a substituted or unsubstituted phenyl group,-   a substituted or unsubstituted phenyl-O—,-   a substituted or unsubstituted phenyl-CO—,-   a substituted or unsubstituted phenyl-lower alkyl group,-   a substituted or unsubstituted phenyl-O-lower alkyl group,-   a substituted or unsubstituted phenylsulfonyl group,-   a substituted or unsubstituted phenyl-lower alkoxy group,-   a substituted or unsubstituted phenyl-lower alkoxycarbonyl group,-   a substituted or unsubstituted cycloalkenyl group (a cyclobutenyl    group, etc.),-   a substituted or unsubstituted bicyclic heterocyclic group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-O—,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-CO—,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-CO-lower alkyl group, and-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-lower alkyl group-   (substituents in the substituted lower cycloalkyl group portion,    substituted phenyl group portion, substituted lower cycloalkenyl    group portion, substituted bicyclic heterocyclic group portion or    substituted monocyclic 5- or 6-membered heterocyclic group portion    are not particularly limited, and examples of which include-   a halogen atom (Cl, F, Br, etc.), cyano group, nitro group, oxo    group and substituents in the substituents of Group C mentioned    below, etc.

Also, a monocyclic 5- or 6-membered heterocyclic group portion includesa monocyclic 5- or 6-membered heterocyclic group containing 1 or 2hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,and specific examples include

-   a piperidyl group, a piperazinyl group, a morpholinyl group, a    pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl    group, a pyrrolidinyl group, an imidazolidinyl group, a    pyrazolidinyl group, a pyrrolyl group, an imidazolyl group, a    pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl    group, etc.

Also, a bicyclic heterocyclic group portion includes a bicyclicheterocyclic group containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom and comprising two 5- or 6-memberedrings being fused, and examples of which include an isoindolinyl group,an indolinyl group, etc.)

Substituents Group A′ (Particularly Preferred Substituents of Group A)

As more preferable substituents of Group A, the following substituentsare mentioned:

-   a halogen atom (Cl, etc.); cyano group; nitro group; oxo group;    carbamoyl group; a lower alkyl group; a lower alkoxy group; a lower    alkanoyl group; a lower alkoxycarbonyl group; a lower    alkoxy-substituted lower alkyl group,-   a mono- or di-substituted amino group (a lower    cycloalkylcarbonyl-substituted amino group, etc.),-   a mono- or di-substituted carbamoyl group (a phenyl-substituted    carbamoyl group, etc.),-   a lower cycloalkyl-CO—,-   a substituted or unsubstituted phenyl group (phenyl group, a    halophenyl group, etc.),-   a substituted or unsubstituted phenyl-lower alkyl group (a    phenyl-lower alkyl group, a halophenyl-lower alkyl group, etc.),-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group (a thienyl group, etc.),-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-O— (a pyrimidinyloxy group, a halo-pyrimidinyloxy    group, etc.), and-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-CO— (a pyridylcarbonyl group, a thienyl-carbonyl    group, etc.).    (In the above description, each monocyclic 5- or 6-membered    heterocyclic group portion includes a monocyclic 5- or 6-membered    heterocyclic group containing 1 or 2 hetero atoms selected from    nitrogen atom, oxygen atom and sulfur atom, and examples of which    include a pyridyl group, a pyrimidinyl group, a thienyl group, etc.)

Substituents of Group B

As substituents of Group B, the following substituents are mentioned:

-   a lower alkyl group; a lower alkoxy-substituted lower alkyl group; a    lower alkoxycarbonyl-substituted lower alkyl group; a hydroxy lower    alkyl group; a carboxy lower alkyl group;-   a substituted or unsubstituted lower cycloalkyl group,-   a substituted or unsubstituted lower cycloalkyl-lower alkyl group,-   a substituted or unsubstituted phenyl group,-   a substituted or unsubstituted phenyl-lower alkyl group,-   a substituted or unsubstituted bicyclic hydrocarbon group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-lower alkyl group, and-   a substituted or unsubstituted bicyclic heterocyclic group-lower    alkyl group-   (substituents in the substituted lower cycloalkyl group portion,    substituted phenyl group portion, substituted bicyclic hydrocarbon    group portion, substituted monocyclic 5- or 6-membered heterocyclic    group portion or substituted bicyclic heterocyclic group portion are    not particularly limited, and examples of which include substituents    in the substituents of Group C mentioned below.

A bicyclic hydrocarbon group portion includes a bicyclic hydrocarbongroup having 9 to 11 carbon atoms, and examples of which include anindanyl group, etc.

Also, a monocyclic 5- or 6-membered heterocyclic group portion includesa monocyclic 5- or 6-membered heterocyclic group containing 1 or 2hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,and examples of which include

-   a piperidyl group, a piperazinyl group, a morpholinyl group, a    pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl    group, a pyrrolidinyl group, an imidazolidinyl group, a    pyrazolidinyl group, a pyrrolyl group, an imidazolyl group, a    pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl    group, etc.

Also, a bicyclic heterocyclic group portion includes a bicyclicheterocyclic group containing 1 to 3 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom and comprising two 5- or 6-memberedrings being fused, and examples of which include a benzodioxolanylgroup, etc.).

Substituents of Group B′ (More Preferred Substituents of Group B)

As more preferred substituents of Group B, the following substituentsare mentioned:

-   a lower alkyl group (methyl group, ethyl group, isopropyl group,    butyl group, etc.), a lower cycloalkyl group, a lower    alkoxy-substituted lower alkyl group, a pyrimidinyl group, a    thiazolyl group, a thiadiazolyl group.

As particularly preferred substituents of Group B, the followingsubstituents are exemplified:

In case that R² is a di-substituted amino group,

-   a lower alkyl group (methyl group, ethyl group, isopropyl group,    butyl group, etc.), a lower cycloalkyl group and a lower    alkoxy-substituted lower alkyl group; and-   in case that R² is a mono-substituted amino group, a pyrimidinyl    group, a thiazolyl group and a thiadiazolyl group.

Substituents of Group C

As substituents of Group C, the following substituents are mentioned:

-   a lower alkyl group; a hydroxy-lower alkyl group; a lower alkanoyl    group; a lower cycloalkylcarbonyl group; a lower alkoxy group; a    lower alkoxycarbonyl group; a lower alkylsulfonyl group; a di-lower    alkyl-substituted carbamoyl group; a di-lower alkylamino-substituted    lower alkanoyl group; and-   a substituted or unsubstituted phenyl group,-   a substituted or unsubstituted phenyl-O—,-   a substituted or unsubstituted phenyl-CO—,-   a substituted or unsubstituted phenyl-lower alkanoyl group,-   a substituted or unsubstituted phenyl-lower alkyl group,-   a substituted or unsubstituted phenyl-lower alkoxy group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group,-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-O— (a pyridyloxy group, etc.),-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-CO— (a pyridylcarbonyl group, etc.), and-   a substituted or unsubstituted monocyclic 5- or 6-membered    heterocyclic group-substituted amino group (a pyridylamino group,    etc.)-   (substituents in the substituted phenyl group portion or substituted    monocyclic 5- or 6-membered heterocyclic group portion are not    particularly limited, and examples of which include-   a halogen atom (Cl, F, Br, etc.), cyano group, nitro group, oxo    group, a lower alkyl group, a lower alkoxy group, a lower alkanoyl    group, and a lower alkoxycarbonyl group, etc.

Also, a monocyclic 5- or 6-membered heterocyclic group portion includesa monocyclic 5- or 6-membered heterocyclic group containing 1 or 2hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom,and examples of which include

-   a piperidyl group, a piperazinyl group, a morpholinyl group, a    pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl    group, a pyrrolidinyl group, an imidazolidinyl group, a    pyrazolidinyl group, a pyrrolyl group, an imidazolyl group, a    pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a thienyl    group, etc.)

In the objective compound [I] of the present invention, as R² when X is—N(R³)— or —O—, a cyclic group which may be substituted may be mentionedas a preferred example.

Also, in the objective compound [I] of the present invention, as R² whenX is —CO—, there may be mentioned (1) a monocyclic, bicyclic ortricyclic nitrogen-containing heterocyclic group which may besubstituted or (2) an amino group which may be substituted, representedby the formula:

as preferred examples.

Also, in the objective compound [I] of the present invention, among thetwo kinds of cis-trans isomers based on a cyclohexyl ring in thestructure [I] as a standard plane, a trans-isomeric compound is morepreferred from the viewpoint of obtaining higher DPPIV inhibitoryactivity. That is, among the objective compound [I] of the presentinvention, a compound having the following partial structure:

or a pharmaceutically acceptable salt thereof is preferred.

In particular, for a compound in which the group X is —CO—, superiorityof such trans isomer is remarkable.

As one compound group of the compounds of the present invention, amongthe compounds [I], those in which R² is

-   (1) a cyclic group which may have 1 to 3 substituents which are the    same or different and selected from the substituents of Group A,    where the cyclic group portion is (i) a monocyclic, bicyclic or    tricyclic hydrocarbon group, or-   (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or-   (2) an amino group having 1 or 2 substituents which are the same or    different and selected from the substituents of Group B can be    mentioned. (Compound Group 1)

Also, as other compound groups, among the compounds [I] or theabove-mentioned Compound Group 1, the compounds in which R² is

-   (1) a cyclic group which may be substituted, where the cyclic group    portion is selected from the following (i) to (iv):-   “(i) a monocyclic hydrocarbon group having 3 to 7 carbon atoms,    -   (ii) a bicyclic hydrocarbon groups having 9 to 11 carbon atoms,-   (iii) a monocyclic heterocyclic group containing 1 or 2 hetero atoms    selected from nitrogen atom, oxygen atom and sulfur atom, and-   (iv) a bicyclic heterocyclic group containing 1 to 3 hetero atoms    selected from nitrogen atom, oxygen atom and sulfur atom and    comprising two 5- to 7-membered rings being fused; or-   (2) a substituted amino group;-   can be mentioned (Compound Group 2).

Also, among the above-mentioned Compound Group 2, the compounds in whichR² is

-   (1) a cyclic group which may be substituted wherein the cyclic group    portion is a group selected from phenyl group, cyclohexyl group,    cyclopentyl group, cyclobutyl group, cyclopropyl group, an indanyl    group, an indenyl group, a naphthyl group, tetrahydronaphthyl, a    pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group,    an oxolanyl group, a thiolanyl group, a pyrrolinyl group, an    imidazolinyl group, a pyrazolinyl group, a pyrrolyl group, an    imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl    group, a furyl group, an oxazolyl group, an isoxazolyl group, an    oxadiazolyl group, a thienyl group, a thiazolyl group, an    isothiazolyl group, a thiadiazolyl group, a piperidyl group, a    piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a    pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl    group, a pyranyl group, a tetrahydropyridyl group, a    dihydropyridazinyl group, a perhydroazepinyl group, a    perhydrothiazepinyl group, an indolinyl group, an isoindolinyl    group, an indolyl group, an indazolyl group, an isoindolyl group, a    benzimidazolyl group, a benzothiazolyl group, a benzoxazolyl group,    a benzodioxolanyl group, a benzothienyl group, a benzofuryl group, a    thienopyridyl group, a thiazolopyridyl group, a pyrrolopyridyl    group, a dihydropyrrolopyridyl group, a quinolyl group, an    isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, a    phthalazinyl group, a cinnolinyl group, a chromanyl group, an    isochromanyl group, a naphthyridinyl group and partially or    completely saturated cyclic groups thereof; or-   (2) a substituted amino group can be mentioned (Compound Group 3).

Also, in Compound Group 3, as more preferred compound group, thecompounds in which R² is

-   (1) a cyclic group which may be substituted, where the cyclic group    portion is a group selected from the group consisting of phenyl    group, cyclohexyl group, a pyrrolidinyl group, a tetrazolyl group, a    furyl group, a thienyl group, a thiazolyl group, a piperidyl group,    a piperazinyl group, a morpholinyl group, a thiomorpholinyl group, a    pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl    group, a perhydroazepinyl group, an indolinyl group, an isoindolinyl    group, a benzothienyl group, a thienopyridyl group, a pyrrolopyridyl    group, a dihydropyrrolopyridyl group, a quinolyl group, an    isoquinolyl group, a quinoxalinyl group and partially or completely    saturated cyclic-groups thereof; or-   (2) a substituted amino group can be mentioned (Compound Group 4).

Also, in Compound Group 4, as more preferred compound group, thecompounds in which R² is

-   (1) a cyclic group which may be substituted wherein the cyclic group    portion is a group selected from a pyrrolidinyl group, a piperidyl    group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl    group, a pyridyl group, a pyrimidinyl group, an indolinyl group, an    isoindolinyl group, a pyrrolopyridyl group, a dihydropyrrolopyridyl    group and partially or completely saturated cyclic groups thereof;    or-   (2) a substituted amino group can be mentioned (Compound Group 5).

Also, among the compounds [I], as another more preferred compound group,the compounds in which R² is

-   (1) a cyclic group which may have 1 to 3 substituents, which are the    same or different, selected from the substituents of Group A′, where    the cyclic group portion is selected from the group consisting of a    pyrrolidinyl group, a piperidyl group, a piperazinyl group, a    morpholinyl group, a thiomorpholinyl group, a pyridyl group, a    pyrimidinyl group, an indolinyl group, an isoindolinyl group, a    pyrrolopyridyl group, a dihydropyrrolopyridyl group and partially or    completely saturated cyclic groups thereof; or-   (2) an amino group substituted by 1 or 2 substituents, which are the    same or different, selected from the substituents of Group B′ can be    mentioned. (Compound Group 6)

Also, among the compounds [I], or among each of the above-mentionedCompound Groups 1, 2, 3, 4, 5 and 6, a compound group in which, when Xis —N(R³)— or —O—, R² is a cyclic group which may be substituted can bementioned.

-   (Compound Group 7)

Also, among the compounds [I], or among each of the above-mentionedCompound Groups 1, 2, 3, 4, 5 and 6, a group of compounds in which, whenX is —CO—, R² is (1) a monocyclic, bicyclic or tricyclicnitrogen-containing heterocyclic group which may be substituted or (2)an amino group which may be substituted, represented by the formula:

can be mentioned. (Compound Group 8)

Also, among the compounds [I] or the above-mentioned Compound Groups 1,2, 3, 4, 5, 6, 7 or 8, as more preferred compound groups,

-   a compound group in which X is —CO— or —O— and A is —CH₂—;-   a compound group in which X is —CO— or —O—, A is —CH₂— and R¹ is    hydrogen atom;-   a compound group in which X is —CO—, A is —CH₂— and R¹ is hydrogen    atom;-   a compound group in which X is —CO—, A is —CH₂—, R¹ is hydrogen atom    and R² is a cyclic group which may be substituted;-   a compound group in which X is —CO—, A is —CH₂—, R¹ is hydrogen atom    and R² is a substituted amino group;-   a compound group in which X is —CO— or —O— and A is —S—;-   a group of compounds in which X is —CO— or —O—, A is —S— and R¹ is    hydrogen atom;-   a compound group in which X is —CO—, A is —S— and R¹ is hydrogen    atom;-   a compound group in which X is —CO—, A is —S—, R¹ is hydrogen atom    and R² is a cyclic group which may be substituted;-   a compound group in which X is —CO—, A is —S—, R¹ is hydrogen atom    and R² is a substituted amino group, etc. may be mentioned.

Also, in each of the above-mentioned compound groups, as a morepreferred compound group, a compound group having the following partialstructure:

can be mentioned.

Also, among the compounds [I], the following compounds can be mentionedas examples of preferred compounds;

(S)-2-cyano-1-[trans-4-(5-nitro-2-pyridylamino)-cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(5-cyano-2-pyridyloxy)-cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(dimethylaminocarbonyl)-cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(morpholinocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(5-bromo-2-pyrimidinyloxy)-cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(5-pyrimidinylaminocarbonyl)-cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(N-ethyl-N-methoxyethylaminocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(N-ethyl-N-isopropylaminocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(N-methyl-N-butylaminocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-[(S)-2-methoxymethylpyrrolidin-1-ylcarbonyl]cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(3-carbamoylpiperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(3-nitro-2-pyridylamino)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(4-acetylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(2-isoindolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-[4-(3-pyridylcarbonyl)piperazin-1-ylcarbonyl]cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-[4-(3-thenoyl)piperazin-1-ylcarbonyl]cyclohexylamino)acetylpyrrolidine;

(S)-2-cyano-1-{trans-4-[4-(4-chlorophenyl)piperazin-1-ylcarbonyl]cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(cis-2,6-dimethylmorpholinocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(5-nitro-2-isoindolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(piperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-(trans-4-(4-carbamoylpiperidinocarbonyl)cyclohexylamino)acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(1-pyrrolidinylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(4-cyclopropylcarbonylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(4-propionylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(1-indolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(2,3-dihydro-1H-pyrrolo[3,4-b]pyridin-2-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-[4-(2-pyrimidinyloxy)-piperidinocarbonyl]cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-(trans-4-[4-(5-bromo-2-pyrimidinyloxy)-piperidinocarbonyl]cyclohexylamino}acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(cis-3,5-dimethyl-4-benzylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(4-cyclohexylcarbonylaminopiperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;—(S)-2-cyano-1-{trans-4-[4-(N-phenylcarbamoyl)-piperazin-1-ylcarbonyl]cyclohexylamino}acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(4-ethoxycarbonylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(S)-2-cyano-1-{trans-4-[4-(2-thienyl)piperidinocarbonyl]cyclohexylamino}acetylpyrrolidine;

(S)-2-cyano-1-[trans-4-(1,1-dioxoperhydro-1,4-thiazin-4-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;

(R)-4-cyano-3-[trans-4-(5-nitro-2-pyridylamino)cyclohexylamino]acetylthiazolidine;

(R)-4-cyano-3-[trans-4-(5-cyano-2-pyridyloxy)cyclohexylamino]acetylthiazolidine;

(R)-4-cyano-3-[trans-4-(dimethylaminocarbonyl)cyclohexylamino]acetylthiazolidine;

(R)-4-cyano-3-[trans-4-(2-isoindolinylcarbonyl)cyclohexylamino]acetylthiazolidine;

(R)-4-cyano-3-[trans-4-(morpholinocarbonyl)cyclohexylamino]acetylthiazolidine;and

(R)-4-cyano-3-[trans-4-(pyrrolidinylcarbonyl)cyclohexylamino]acetylthiazolidine.

The objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention has superior inhibitory action on the enzymeactivity of DPPIV. They have superior inhibitory action especially onhuman DPPIV. In addition, they also exhibit high selectivity withrespect to DPPIV (namely, type IV dipeptidylpeptidase) in various serineproteases (e.g., plasmin, thrombin, prolylendopeptidase, trypsin anddipeptidylpeptidase II).

Also, the objective compound [I] or a pharmaceutically acceptable saltthereof of the present invention improves insulin secretion response tooral glucose loading by means of its DPPIV inhibitory action.

Thus, the objective compound [I] or a pharmaceutically acceptable saltthereof of the present invention is useful as prophylactic ortherapeutic agents for diseases relating to DPPIV (diseases mediated byDPPIV), that is, diseases which is expected to be alleviated byinhibiting DPPIV enzyme activity. Examples of such diseases includediabetes (e.g., type 1 diabetes and type 2 diabetes), hyperglycemia(such as postprandial hyperglycemia), hyperinsulinemia, diabetescomplications (such as renal disorder and neurological disorder),obesity, overeating, lipid metabolism disorder (such as hyperlipemiaincluding hypertriglyceridemia and others), autoimmune diseases (such asarthritis and rheumatoid arthritis), osteoporosis, acquiredimmunodeficiency syndrome (AIDS) and rejection of transplanted organsand tissues.

The objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention is particularly useful as a prophylactic ortherapeutic agent of diabetes (and particularly type 2 diabetes).

Also, the compound of the present invention has low toxicity, and thus,has a high degree of safety when used as a pharmaceutical compound.Also, it also demonstrates superior pharmacokinetic characteristics[including bioavailability, in vitro metabolic stability (stability inhuman liver homogenates), P450 inhibitory action, protein bindingcapabilities, etc.].

The DPPIV inhibitory action of the compound of the present invention aswell as its pharmaceutical efficacy (including anti-hyperglycemia effectand the effect of improving insulin secretion response to glucoseloading) based on that action can be confirmed by known methods ormethods equivalent to those methods (WO98/19998; WO00/34241; Holst, etal., Diabetes, Vol. 47, pp. 1663–1670, 1998; Augustyns, et al., CurrentMedicinal Chemistry, Vol. 6, pp. 311–327, 1999; Meester, et al.,Immunol. Today, Vol. 20, pp. 367–375, 1999; and, Fleicher, et al.,Immunol. Today, Vol. 15, pp. 180–184, 1994).

The objective compound [I] of the present invention can be used for apharmaceutical use either in a free form or in a form of apharmaceutically acceptable salt. Examples of the pharmaceuticallyacceptable salt of the compound [I] include an inorganic acid salt suchas hydrochloride, sulfate, phosphate or hydrobromide, and an organicacid salt such as acetate, fumarate, oxalate, citrate, methanesulfonate,benzenesulfonate, tosylate or maleate, etc. In addition, in case that acompound has a substituent(s) such as carboxyl group, a salt with a base(for example, an alkali metal salt such as a sodium salt, a potassiumsalt, etc., or an alkaline earth metal salt such as a calcium salt andthe like) may be mentioned.

The objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention includes its internal salt, an adduct, asolvate and a hydrate.

The objective compound [I] or a pharmaceutically acceptable salt thereofof the present invention can be administered orally or parenterally andused as commonly used pharmaceutical preparations such as a tablet,granule, capsule, powder, injection solution and inhalant. For example,the compound of the present invention can be used with an excipient or adiluent acceptable for general pharmaceuticals such as a binder,disintegrator, extender, filler and lubricant, to form a preparationaccording to the usual method.

The administration dose of the objective compound [I] or apharmaceutically acceptable salt thereof of the present invention mayvary depending on the administration method, age, weight and conditionof a patient, and it is generally about 0.01 to 300 mg/kg, particularlypreferably about 0.1 to 30 mg/kg per day.

The objective compound [I] of the present invention can be preparedaccording to the following (Process A) and (Process B), but it is notlimited to these processes.

(Process A)

The objective compound [I] of the present invention can be prepared byreacting a compound represented by the formula [II]:

-   -   wherein Z¹ represents a reactive residue and A has the same        meaning as defined above,        with a compound represented by the formula [III]:

-   -   wherein R¹, R² and X have the same meanings as defined above,        or a salt thereof, and optionally, by making the product into a        pharmaceutically acceptable salt.

As examples of the salt of the compound [III], a salt with an inorganicacid such as hydrochloride and sulfate, or a salt with an inorganic basesuch as an alkali metal salt and an alkaline earth metal salt can beused.

As the reactive residue of Z¹, commonly used reactive residues such as ahalogen atom, a lower alkylsulfonyloxy group and an arylsulfonyloxygroup can be used, among which the halogen atom is particularlypreferred.

The reaction of the compound [II] with the compound [III] or the saltthereof can be carried out in a suitable solvent or without solvent inthe presence or absence of an acid acceptor.

As the solvent, any solvents may be suitable as long as it does notadversely affect to the reaction, and, for example, acetonitrile,methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone,dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, ether, dioxane,ethyl acetate, toluene, methylene chloride, dichloroethane, chloroformor a mixed solvent of these solvents can be suitably used.

This reaction suitably proceeds at 0 to 120° C., particularly at roomtemperature to 80° C.

As the acid acceptor, an inorganic base (for example, alkali metalhydride such as sodium hydride, alkali metal carbonate such as sodiumcarbonate and potassium carbonate, alkali metal alkoxide such as sodiummethoxide, alkali metal such as sodium, and alkali metal hydroxide suchas sodium hydroxide and potassium hydroxide, etc.) or an organic base(for example, triethylamine, diisopropylethylamine, N-methylmorpholine,pyridine, dimethylaniline, dimethylaminopyridine, etc.) can be suitablyused.

(Process B)

In addition, among the objective compound [I] of the present invention,

the compound represented by the formula [I-a]:

-   -   wherein R²¹ represents (1) a monocyclic, bicyclic or tricyclic        nitrogen-containing heterocyclic group which may be substituted        or (2) an amino group which may be substituted, and represented        by the formula:

-   -   and R¹ and A have the same meanings as defined above, can be        prepared by reacting a compound represented by the formula [IV]:

-   -   wherein R⁴ represents a protective group for an amino group, and        R¹ and A have the same meanings as defined above,        or a salt thereof with the compound represented by the formula        [V]:        R²¹—H        or a salt thereof to obtain a compound represented by the        formula [VI]:

-   -   wherein R¹, R⁴, R²¹ and A have the same meanings as defined        above,        or a salt thereof, and by removing the protective group for the        amino group (R⁴) from the product, and optionally, by making the        product into a pharmaceutically acceptable salt.

As examples of salts of the compounds [IV] to [VI], a salt with aninorganic acid such as hydrochloride and sulfate, or a salt with aninorganic base such as an alkali metal salt and an alkaline earth metalsalt can be used.

As the protective group for the amino group of R⁴, any of the commonlyused protective groups for the amino group such as t-butoxycarbonylgroup, benzyloxycarbonyl group, trifluoroacetyl group, chloroacetylgroup, 9-fluorenylmethyloxycarbonyl group, etc. can be suitably used.

The reaction of the compound [IV] or a salt thereof with the compound[V] or a salt thereof can be carried out in a suitable solvent orwithout solvent in the presence or absence of a condensing agent.

As the solvent, any solvents may be suitable as long as it does notadversely affect to the reaction, and, for example, acetonitrile,methanol, ethanol, isopropyl alcohol, propyl alcohol, acetone,dimethylformamide, tetrahydrofuran, ether, dioxane, ethyl acetate,toluene, methylene chloride, dichloroethane, chloroform or a mixedsolvent of these solvents can be suitably used.

This reaction suitably proceeds at 0 to 120° C., particularly at roomtemperature to 80° C.

For the condensing agent,O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, DCC(dicyclohexylcarbodiimide), EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), chloroformates (forexample, ethyl chloroformate and isobutyl chloroformate) andcarbonyldiimidazole can be suitably used.

Also, for promoting the reaction, additives such as base (sodiumcarbonate, sodium hydrogencarbonate, triethylamine, pyridine,4-dimethylaminopyridine, diisopropylethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), 1-hydroxybenzotriazole,1-hydroxysuccinimide, etc. can be added to the above condensing agents.

The subsequent removal of the protective group (R⁴) for the amino groupof the compound [VI] can be carried out according to the conventionalmethod, and it can be carried out, for example, in a suitable solvent orwithout solvent by an acid treatment, base treatment or catalyticreduction.

As the solvent, any solvents may be suitable as long as it does notadversely affect to the reaction, and, for example, methanol, ethanol,isopropyl alcohol, propyl alcohol, dioxane, methylene chloride,chloroform, dichloroethane, ether, tetrahydrofuran, ethyl acetate,toluene or a mixed solvent of these solvents can be suitably used.

This reaction suitably proceeds at −78 to 80° C., particularly at 0° C.to room temperature.

As the acid, an inorganic acid such as hydrochloric acid, sulfuric acid,etc., and an organic acid such as acetic acid, trifluoroacetic acid,methanesulfonic acid, p-toluenesulfonic acid, etc. can be suitably used.

As the base, an inorganic base (for example, alkali metal hydride suchas sodium hydride, etc., alkali metal carbonate such as sodiumcarbonate, potassium carbonate, etc., alkali metal alkoxide such assodium methoxide, etc., alkali metal such as sodium, etc., and alkalimetal hydroxide such as sodium hydroxide, potassium hydroxide, etc.) oran organic base (for example, triethylamine, diisopropylethylamine,morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline,dimethylaminopyridine, etc.) can be suitably used.

The catalytic reduction can be carried out by suitably usingpalladium-carbon, palladium hydroxide-carbon, platinum oxide or Raneynickel under hydrogen atmosphere.

The starting material [II] of the present invention can be prepared, forexample, according to the method described in International PatentPublications Nos. WO 98/19998, WO 00/34241, Reference Examples(Reference Example 1 or 2) mentioned below and the like.

For example, the compound [II] can be obtained by reacting a compoundrepresented by the formula [10]:

-   -   wherein A has the same meaning as defined above, with a compound        represented by the formula [11]:        Z²—CH₂CO—Z³  [11]    -   wherein Z² and Z³ represent reactive residues which may be the        same or different,        in the presence of an acid acceptor (for example, triethylamine)        to obtain a compound represented by the formula [12]:

-   -   wherein Z² and A have the same meanings as defined above,        and treating the product with a dehydrating agent (for example,        phosphorous oxychloride, trifluoroacetic anhydride, etc.)        according to the conventional method.

As the reactive residue of Z² or Z³, the same reactive residue commonlyused as in the above Z¹ can be suitably used.

The starting material [III] can be prepared, for example, by the samemethod as described in Reference Examples (Reference Examples 3 to 14)mentioned below.

For example, the compound [III] in which X is —N(R³)— or —O— can beprepared by reacting-a compound represented by the formula [13]:

-   -   wherein V¹ represents —NH(R³)— or hydroxy group, and R¹ and R³        have the same meanings as defined above,        an amino group-protected material thereof or a salt thereof with        a compound represented by the formula [14]:        R²—Z⁴  [14]    -   wherein Z⁴ represents a reactive residue and R² has the same        meaning as defined above,        in the presence or absence of an acid acceptor (for example, an        organic base such as triethylamine, diisopropylethylamine, etc.,        and an inorganic base such as sodium hydride, potassium        carbonate, etc.), and, if necessary, by removing the protective        group for the amino group according to the conventional method.

As the protective group for the amino group, any of the same protectivegroups commonly used as in the above R⁴ can be suitably used.

As the reactive residue of Z⁴, the same reactive residues commonly usedas in the above Z¹ can be suitably used.

For example, the compound [III] in which X is —CO— and R² is a grouprepresented by the formula:

can be produced by reacting a compound represented by the formula [15]:

-   -   wherein V² represents —COOH and R¹ has the same meaning as        defined above,        an amino group-protected material thereof or a salt thereof with        a compound represented by the formula [16]:        R²²—H  [16]    -   wherein R²² represents (1) a monocyclic, bicyclic or tricyclic        nitrogen-containing heterocyclic group which may be substituted        or (2) an amino group which may be substituted, represented by        the formula:

-   -   and forms a cyclic or straight amine together with hydrogen        atom,        or a salt thereof, in the presence of a condensing agent        (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, etc.) and, if        necessary, by removing the protective group for the amino group        according to the conventional method.

Or else, the compound [III] in which X is —CO— can be obtained byreacting a compound represented by the formula [17]:

-   -   wherein Z⁵ represents a reactive residue and R¹ has the same        meaning as defined above,        an amino group-protected material thereof or a salt thereof with        a compound represented by the formula [18]:        R²—Sn(R⁵)₃  [18]    -   wherein R⁵ represents a lower alkyl group and R² has the same        meaning as defined above,        in the presence of a palladium catalyst (for example,        dichlorobis(triphenylphosphine)palladium, etc.).

As the protective group for the amino group, any of the same protectivegroups commonly used as in the above R⁴ can be suitably used. Also, asthe reactive residue of Z⁵, the same reactive residues commonly used asin the above Z¹ can be suitably used.

Or else, the compound [III] in which X is —N(R³)— can be prepared byreacting the compound represented by the formula [19]:

-   -   wherein R¹ has the same meaning as defined above, an amino        group-protected material thereof or a salt thereof with the        compound represented by the formula [20]:        R²—V³  [20]    -   wherein V³ represents —N(R³) H and R² has the same meaning as        defined above,        in the presence of a reducing agent (sodium        triacetoxyborohydride, etc.) and, if necessary, by removing the        protective group for the amino group according to the        conventional method.

As the protective group for the amino group, any of the same protectivegroups commonly used as in the above R⁴ can be suitably used.

The starting materials [10] to [20] can be prepared according to knownmethods or in the same manner as described in Reference Examplesmentioned below.

In order to obtain a trans form of the starting material [III] taking acyclohexane ring as a standard plane, each trans form of the startingcyclohexane compounds (the compounds [13], [15], [17], etc.) may beused.

Also, the starting material [IV] can be prepared, for example, in thesame manner as in the process described in Example (Example 3-1, (1) to(3)) mentioned below or in accordance with these processes, as shown inthe following figure. (In the figure, Z⁶ represents a reactive residue,R⁴ represents a protective group for an amino group and other symbolshave the same meanings as defined above.)

As the reactive residue of Z⁶, the same reactive residues commonly usedas in the above Z¹ can be suitably used.

The compound [I] of the present invention or its starting materialprepared according to the above is isolated in a free form or as a saltthereof, and purified. The salt can be prepared by subjecting to thesalt-forming treatment conventionally used.

Isolation and purification can be carried out by applying the usualchemical operations such as extraction, concentration, crystallization,filtration, recrystallization, various kinds of chromatographies and thelike.

In the compound of the present invention, optical isomers such asracemic isomers, optically active isomers, diastereomers, etc. can bepresent alone or as mixtures thereof. A stereochemically pure isomer canbe derived by using a stereochemically pure starting material or byseparating an optical isomer according to the general separation processfor racemic resolution. Also, diastereomeric mixtures can be separatedaccording to the conventional method, for example, fractionalcrystallization or by chromatography.

EXAMPLES

The present invention will be described in detail by referring to thefollowing Examples but these Examples do not intend to limit the presentinvention.

Example 1a-1

A acetonitrile-methanol solution containing 100 mg of(S)-1-bromoacetyl-2-cyanopyrrolidine (Reference Example 1 mentionedbelow) and 327 mg of N-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine(Reference Example 3-1 mentioned below) was stirred at room temperaturefor 15 hours. Water was added to the reaction mixture and the mixturewas extracted with chloroform. After the extract was dried over sodiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by diol column chromatography (solvent: 0 to 10%methanol-chloroform) to obtain an oily product. The oily product wasdissolved in 0.5 ml of ethyl acetate-0.5 ml of chloroform, and then, 1.0ml of 2N hydrochloric acid-ether and 2 ml of ether were successivelyadded thereto. Precipitates were collected by filtration and washed withether to obtain(S)-2-cyano-1-[trans-4-(5-nitro-2-pyridylamino)cyclohexylamino]acetylpyrrolidine-dihydrochloride(Example 1a-1 in Table 1a).

Examples 1a-2 to 1d-152

Using (S)-1-bromoacetyl-2-cyanopyrrolidine and corresponding startingmaterials, they were treated in the same manner as in Example 1a-1,compounds of Tables 1a to 1d shown below (Examples 1a-2 to 1a-89, 1b-1to 1b-71, 1c-1 to 1c-52 and 1d-1 to 152) were obtained. Incidentally,the corresponding starting materials were obtained by the similar methodas described in Reference Examples mentioned below, by known methods orby a method in combination of these methods.

Provided that the compound of Example 1d-77 was obtained by usingtrans-4-(1-piperazinylcarbonyl)cyclohexylamine as a starting material.

Also, the compound of Example 1c-39 (namely,(S)-2-cyano-1-{trans-4-[(N-carboxymethyl-N-methylamino)carbonyl]-cyclohexylamino}acetylpyrrolidine.hydrochloride)was obtained by treating the compound of Example 1c-38 (namely,(S)-2-cyano-1-{trans-4-[(N-tert-butoxycarbonylmethyl-N-methylamino)carbonyl]cyclohexylamino}acetylpyrrolidine)with trifluoroacetic acid, followed by treating with hydrochloric acid.

Also, the compound of the Example 1d-14 (namely,(S)-2-cyano-1-[trans-4-(1-piperazinylcarbonyl)cyclohexylamino]-acetylpyrrolidine-dihydrochloride)was obtained by treating a free form of the compound of Example 1d-70((S)-2-cyano-1-[trans-4-(4-benzyloxycarbonyl-1-piperazinylcarbonyl)cyclohexylamino]acetylpyrrolidine)with trimethylsilyl iodide.

Examples 2-1 and 2-2

(1) A mixture of 600 mg of4-tert-butoxycarbonylamino-4-methylcyclohexanone (the compound ofReference Example 6-1, (3)), 783 mg of sodium triacetoxyborohydride, 343mg of 3-cyanoaniline, 159 mg of acetic acid and 6 ml of dichloroethanewas stirred at room temperature for 16 hours. The mixture was dilutedwith an aqueous saturated sodium hydrogencarbonate solution and thenextracted with chloroform. The extract was dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (solvent:hexane-ethylacetate (4:1) to (1:1)) to obtain 304 mg ofN-tert-butoxycarbonyl-1-methyl-c-4-(3-cyano-phenylamino)-r-1-cyclohexylamineand 292 mg ofN-tert-butoxycarbonyl-1-methyl-t-4-(3-cyano-phenylamino)-r-1-cyclohexylamine.(2) 243 mg ofN-tert-butoxycarbonyl-1-methyl-c-4-(3-cyanophenylamino)-r-1-cyclohexylamineobtained in the above (1) was stirred in a mixture of 2 ml of 4Nhydrochloric acid/dioxane and 2 ml of ethanol at room temperature for 15hours.

After the reaction mixture was concentrated, to the residue were added320 mg of (S)-1-bromoacetyl-2-cyanopyrrolidine, 0.6 ml of triethylamine,3.5 ml of acetonitrile and 1 ml of methanol and the mixture was stirredat room temperature for 15 hours. The mixture was diluted with anaqueous saturated sodium hydrogencarbonate solution and extracted withchloroform. The extract was dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The residue was purified bysilica gel column chromatography (solvent: chloroform-methanol (50:1))to obtain 154 mg of the compound, which was then treated withhydrochloric acid to yield(S)-2-cyano-1-[1-methyl-c-4-(3-cyano-phenylamino)-r-1-cyclohexylamino]acetylpyrrolidine-dihydrochloride(Table 2: Example 2-1).

(3) UsingN-tert-butoxycarbonyl-1-methyl-t-4-(3-cyanophenylamino)-r-1-cyclohexylamineobtained in the above (1), it was treated in the same manner as in (2),(S)-2-cyano-1-[1-methyl-c-4-(3-cyano-phenylamino)-r-1-cyclohexylamino]-acetylpyrrolidine-dihydrochloride(Example 2-2 in Table 2) was obtained.

Examples 2-3 to 2-8

Using corresponding starting materials, they were treated in the samemanner as in Examples 2-1 to 2-2, compounds of Examples 2-3 to 2-8 shownin Table 2 were obtained.

Example 3-1

(1) In water was dissolved 5.0 g oftrans-4-ethoxycarbonylcyclohexylamine.dihydrochloride, and after thesolution was made basic by adding potassium carbonate, the solution wasextracted with chloroform. The extract was washed with brine, dried overanhydrous sodium sulfate, and the solvent was removed under reducedpressure. A mixture of the residue, 5.1 g of p-toluensulfonic acidmonohydrate and 50 ml of allyl alcohol was refluxed for 48 hours. Thereaction mixture was concentrated, and then, diluted with chloroform.The chloroform solution was washed with an aqueous potassium carbonatesolution, water and brine, dried over anhydrous sodium sulfate, andconcentrated under reduced pressure. The residue was purified by silicagel flash column chromatography (solvent: chloroform-methanol-aqueousammonia (500:10:1)) to obtain 3.29 g oftrans-4-(2-propenyloxycarbonyl)cyclohexylamine.(2) A mixture of 507 mg of the compound obtained in the above (1), 400mg of (S)-1-bromoacetyl-2-cyanopyrrolidine, 714 mg ofN,N-diisopropylethylamine and 4 ml of acetonitrile was stirred at 50° C.for 12 hours. After cooling to room temperature, 476 mg ofN,N-diisopropylethylamine, followed by 4 ml of acetonitrile solutioncontaining 803 mg of di-tert-butyldicarbonate were added to the reactionmixture, and the mixture was stirred at room temperature for 3 hours.After the reaction mixture was concentrated, the concentrate was dilutedwith ethyl acetate. The ethyl acetate solution was washed with anaqueous 10% citric acid solution, water and brine, dried over anhydroussodium sulfate, and concentrated under reduced pressure. The residue waspurified by silica gel flash chromatography (solvent:chloroform-methanol (100:1)) to obtain 658 mg of(S)-2-cyano-1-[N-tert-butoxycarbonyl-trans-4-(2-propenyloxycarbonyl)cyclohexylamino]acetylpyrrolidine.(3) A mixture of 600 mg of the compound obtained in the above (2), 165mg of tetrakis(triphenylphosphine)palladium, 271 mg of ammonium formateand 6 ml of dioxane was stirred at 50° C. for 1 hour. After cooling, thereaction mixture was poured into water and extracted with chloroform.The extract was washed with brine, dried over anhydrous sodium sulfate,and then, the solvent was removed under reduced pressure. The residuewas purified by silica gel flash chromatography (solvent:chloroform-methanol (50:1)) to obtain 394 mg of(S)-2-cyano-1-(N-tert-butoxycarbonyl-trans-4-carboxycyclohexylamino)acetylpyrrolidine.(4) A solution of 2 ml N,N-dimethylformamide containing 150 mg of thecompound obtained in the above (3), 64 mg of 2-aminomethylpyridine, 114mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide and 80 mg of1-hydroxybenzotriazole was stirred at room temperature for 24 hours. Anaqueous saturated sodium hydrogencarbonate solution was added to thereaction mixture and the mixture was extracted with chloroform. Theextract was washed with brine and dried over anhydrous sodium sulfateand the solvent was removed under reduced pressure. The residue wasdissolved in 3 ml of acetonitrile, and 1 ml of an acetonitrile solutionof 118 mg of trimethylsilyl iodide was added dropwise to the solutionunder ice-cooling, and the mixture was stirred at room temperature for30 minutes. To the reaction mixture were added methanol and water, andafter stirring for a while, the mixture was neutralized with an aqueoussaturated sodium hydrogencarbonate solution, and then, extracted withchloroform. The extract was washed with an aqueous saturated sodiumhydrogencarbonate solution, water and brine, dried over anhydrous sodiumsulfate, and then, the solvent was removed under reduced pressure. Theresidue was purified by diol chromatography (solvent:chloroform) toobtain an oily product. The oily product was dissolved in 1 ml of ethylacetate, and then, 0.5 ml of 1N hydrochloric acid-ether followed by 2 mlof ether were added thereto, and precipitates were washed with ether toobtain 106 mg of(S)-2-cyano-1-[trans-4-(2-pyridylmethylaminocarbonyl)cyclohexylamino]acetylpyrrolidine-dihydrochloride(Example 3-1 in Table 3).

Examples 3-2 to 3-12

The compounds of Examples 3-2 to 3-12 in Table 3 were obtained in thesame manner as in Example 3-1 (4), using(S)-2-cyano-1-(N-tert-butoxycarbonyl-trans-4-carboxycyclohexylamino)acetylpyrrolidine(the compound of the above Example 3-1 (3)) and the correspondingstarting materials.

Examples 4-1 to 4-32

A solution of 2 ml of acetonitrile-1 ml of methanol containing 100 mg of(R)-3-chloroacetyl-4-cyanothiazolidine (the compound of ReferenceExample 2 mentioned below) and 372 mg ofN-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine was stirred at roomtemperature for 15 hours. Water was added to the reaction mixture andthe mixture was extracted with chloroform. After the extract was driedover anhydrous sodium sulfate, the solvent was removed under reducedpressure. The residue was purified by diol column chromatography(solvent: 0 to 5% methanol-chloroform) to obtain an oily product. Theoily product was dissolved in 0.5 ml of ethyl acetate-0.5 ml ofchloroform, and 1.0 ml of 2N hydrochloric acid-ether was added thereto,followed by 2 ml of ether. Precipitates were collected by filtration andwashed with ether to obtain 173 mg of(R)-4-cyano-3-[trans-4-(5-nitro-2-pyridylamino)cyclohexylamino]-acetylthiazolidine-dihydrochloride(Example 4-1 in Table 4).

Also, the compounds of Examples 4-2 to 4-32 in Table 4 were obtained inthe same manner as mentioned above, using the corresponding startingmaterials.

Reference Example 1

According to the process described in the literature (WO98/19998),(S)-1-bromoacetyl-2-cyanopyrrolidine was obtained by reactingL-prolineamide (commercially available product) and bromoacetyl bromide,followed by dehydration.

Reference Example 2

L-thioprolineamide hydrochloride was synthesized according to theprocess described in the literature (Ashworth et. al., Bioorg. Med.Chem. Lett., Vol. 6, pp. 2745–2748, 1996). 2.36 ml of chloroacetylchloride was added to a solution of 150 ml of dichloromethane containing5.00 g of L-thioprolineamide hydrochloride thus obtained and 8.67 ml oftriethylamine under ice-cooling, and the mixture was stirred at the sametemperature for 1 hour. To the reaction mixture was added adichloromethane solution containing 4.8 ml of pyridine and 8.4 ml oftrifluoroacetic anhydride, and the mixture was further stirred at roomtemperature for 1 hour. The reaction mixture was washed with an aqueous10% HCl solution and water, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure, and subsequently, theresidue was crystallized from ether to obtain 4.82 g of(R)-3-chloroacetyl-4-cyanothiazolidine as yellow-brownish crystals.

Reference Examples 3-1 to 3-40

A solution of 5-nitro-2-chloropyridine (2.50 g) andtrans-1,4-cyclohexanediamine (5.40 g) in ethanol (15 ml)tetrahydrofuran(10 ml) was stirred at room temperature for 5 days. The precipitateswere removed by filtration and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (solvent: chloroform-methanol-concentrated aqueousammonia (20:4:1)) and crystallized from ethyl acetate to obtainN-(5-nitro-2-pyridyl)-trans-1,4-cyclohexanediamine (Reference Example3-1 in Table 5).

Also, the compounds of Examples 3-2 to 3-40 in Table 5 were obtained inthe same manner as mentioned above, using the corresponding startingmaterials.

Reference Examples 3-41 to 3-44

A N,N-dimethylacetamide (30 ml) solution containing 4-nitrofluorobenzene(1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) was stirred at 144-Cfor 3 days. After cooling, an aqueous saturated potassium carbonatesolution was added to the reaction solution, and the reaction mixturewas extracted with ethyl acetate. The extract was dried over anhydrouspotassium carbonate, and then, the solvent was removed under reducedpressure. The residue was purified by silica gel flash columnchromatography (solvent: chloroform-methanol-ammonia (90:10:1)), and thesolvent was removed to obtaintrans-N-(4-nitrophenyl)-1,4-cyclohexanediamine (Reference Example 3-41in Table 5) (2.31 g).

Also, the compounds of Examples 3-42 to 3-44 in Table were obtained inthe same manner as mentioned above, using the corresponding startingmaterials.

Reference Examples 3-45 to 3-47

25 mL of an ethanol solution containing 1.23 g ofN-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine, 1.0 g of2-chloro-3-nitro-pyridine 1-oxide and 700 mg of dimethylaminopyridinewas refluxed under argon atmosphere for 2 hours.

After cooling, the reaction solution was concentrated under reducedpressure, the residue was dissolved in chloroform, washed with water,dried over anhydrous sodium sulfate, and then, the solvent was removedunder reduced pressure. The obtained residue was purified by silica gelflash column chromatography (solvent: chloroform-methanol (30:1)) toobtain red powder. The resulting compound was dissolved in 5 mL oftrifluoroacetic acid and the solution was stirred at room temperaturefor 3 hours. After the solvent was removed under reduced pressure, theresidue was purified by silica gel flash column chromatography(solvent:aqueous ammonia-saturated chloroform-methanol (10:1)) to obtain110 mg of N-(3-nitropyridine-1-oxid-2-yl)-trans-1,4-cyclohexanediamine(Reference Example 3-45 in Table 5).

Also, the compounds of Examples 3-46 to 3-47 in Table 5 were obtained inthe same manner as mentioned above, using corresponding startingmaterials.

Reference Examples 3-48 to 3-49

In the mixed solvent of 5 ml of ethanol and 4 ml of tetrahydrofuran weredissolved 168 mg ofN-tert-butoxycarbonyl-trans-4-[(6-chloro-3-pyridazinyl)amino]cyclohexylamine(Reference Example 3-46) and 0.5 ml of triethylamine. To the solutionwas added 50 mg of 10% palladium carbon and the mixture was stirredunder hydrogen atmosphere with normal pressure at room temperature for 1day. After the catalyst was removed by filtration, the solvent wasremoved, and the residue was stirred in 2 ml of trifluoroacetic acid for3 hours. The solvent was removed, an aqueous 10% sodium hydroxidesolution was added to the residue, the mixture was extracted withchloroform and dried over anhydrous sodium sulfate. Subsequently, thesolvent was removed under reduced pressure to obtain 61 mg oftrans-4-(pyridazin-3-ylamino)cyclohexylamine (Reference Example 3-48 inTable 5).

Also, the compound of Example 3-49 in Table 5 was obtained by treatingthe corresponding starting material (Reference Example 3-47) in the samemanner as mentioned above.

Reference Examples 3-50 to 3-58

Also, the compounds of Examples 3-50 to 3-58 in Table 5 were obtained inthe same manner as in Reference Example 9-50 or Reference Example 9-55.

Reference Example 3-59

Ethyl 4-chloro-2-phenyl-5-pyrimidinecarboxylate andN-tert-butoxycarbonyl-trans-1,4-cyclohexanediamine were reacted inethanol in the presence of dimethylaminopyridine in the same manner asin Reference Example 3-49 to obtainN-tert-butoxycarbonyl-trans-4-(5-ethoxycarbonyl-2-phenyl-4-pyrimidinylamino)cyclohexylamine.

The compound was treated in the same manner as in Reference Example 9-56(1) and (2) to obtaintrans-4-(5-morpholinocarbonyl-2-phenyl-4-pyrimidinylamino)cyclohexylamine(Reference 3-59 in Table 5).

Reference Example 4

(1) To 150 ml of a tetrahydrofuran suspension containing 10 g oftrans-4-aminocyclohexanol was added 15 ml of triethylamine, 50 ml of atetrahydrofuran solution containing 2-chloro-5-nitropyridine was furtheradded thereto under ice-cooling, and then, the mixture was stirred atroom temperature for 18 hours. Water was added to the reaction mixtureand the mixture was extracted with chloroform. The extract was washedwith brine, dried over anhydrous sodium sulfate, and the solvent wasremoved under reduced pressure. The residue was purified by silica gelflash column chromatography (solvent: ethyl acetate-hexane (2:1)) toobtain 8.52 g of trans-4-(5-nitro-2-pyridylamino)cyclohexanol.(2) To 10 ml of a dichloromethane solution containing 1.0 g of thecompound obtained in the above (1) was added 1.8 ml of triethylamine,0.65 ml of methanesulfonyl chloride was further added thereto underice-cooling, and the mixture was stirred for 1 hour. An aqueoussaturated sodium bicarbonate solution was added to the reaction mixtureand the mixture was extracted with chloroform. The extract was washedwith water and brine, dried over anhydrous sodium sulfate, and then, thesolvent was removed under reduced pressure. 1.37 g of sodium azide wasadded to a solution of the residue dissolved in 10 ml ofdimethylformamide and the mixture was stirred at 50° C. for 3 days.After cooling, an aqueous saturated sodium bicarbonate solution wasadded to the reaction mixture and the mixture was extracted with ethylacetate. The extract was washed with water and brine, dried over sodiumsulfate, and then, the solvent was removed under reduced pressure. Theresidue was purified by silica gel flash column chromatography (solvent:ethyl acetate-hexane (1:5)) to obtain 758 mg ofcis-4-azide-N-(5-nitro-2-pyridyl)cyclohexylamine.(3) A solution comprising 10 ml of tetrahydrofuran-1 ml of water,containing 640 mg of the compound obtained in the above (2) and 704 mgof triphenylphosphine was stirred at room temperature for 2 days. Thereaction mixture was concentrated, and the residue was purified bysilica gel flash column chromatography (solvent: ethyl acetatemethanol(10:1)) to obtain 531 mg ofN-(5-nitro-2-pyridyl)-cis-1,4-cyclohexanediamine (the compound ofReference Example 4 in Table 5).

Reference Examples 5-1 to 5-6

(1) In 600 mL of dimethylformamide were suspended 60.0 g oftrans-4-tert-butoxycarbonylaminocyclohexyl methanesulfonate and 20.1 gof sodium azide and the suspension was stirred at 90° C. for 6 hours.The reaction mixture was poured into water and extracted with ethylacetate. The extract was washed with water and brine, dried overanhydrous sodium sulfate, and then, the solvent was removed underreduced pressure to obtain 47.9 g ofcis-4-azide-N-(tert-butoxycarbonyl)cyclohexylamine.(2) In 8 mL of tetrahydrofuran were suspended 500 mg of the compoundobtained in the above (1) and 100 mg of palladium-carbon (wet) and thesuspension was vigorously stirred under hydrogen atmosphere at roomtemperature for 1.5 hours. During the course, hydrogen in the system wasreplaced twice. The insolubles were removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (solvent:chloroform-methanol(20:1), followed by chloroform-methanol-aqueous ammonia (100:10:1)) toobtain 395 mg of N-tert-butoxycarbonyl-cis-1,4-cyclohexanediamine.(3) A suspension comprising 10 mL of 2-propanol, 2.0 g of the compoundobtained in the above (2), 1.63 g of 2-chloro-3-nitropyridine and 1.95mL of diisopropylethylamine was stirred at 80° C. for 1 day. After thereaction mixture was concentrated under reduced pressure, water wasadded thereto and the mixture was extracted with ethyl acetate. Theextract was washed with brine, dried over anhydrous sodium sulfate, andthen, the solvent was removed under reduced pressure. The residue waspurified by silica gel chromatography (solvent: chloroform, followed bychloroform-ethyl acetate (7:1)). To a suspension of the resultantcompound in ethanol was added hydrochloric acid-dioxane, the mixture wasstirred at room temperature for 18 hours, and the precipitates werecollected by filtration to obtain 2.15 g ofN-(3-nitro-2-pyridyl)-cis-1,4-cyclohexanediamine dihydrochloride(Reference Example 5-1 in Table 5).

Also, the compounds of Reference Examples 5-2 to 5-6 in Table 5 wereobtained in the same manner as mentioned above, using the correspondingstarting materials.

Reference Example 6-1

(1) According to the process described in the literature (JP83-118577),methyl 1,4-dioxaspiro[4.5]decan-8-carboxylate was reacted with methyliodide in the presence of LDA (lithium diisopropylamide) to obtainmethyl 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylate (the compound (1)of the above figure).(The starting materials were synthesized according to the processdescribed in the literature by Rosemmund et al. (Chem. Ber., 1975, Vol.108, pp. 1871–1895) and the literature by Black et al. (Synthesis, 1981,p. 829).)(2) A mixture of 3.80 g of the compound obtained in the above (1), 3.55g of sodium hydroxide, 16 mL of methanol and 25 mL of water was refluxedfor 2 hours. The reaction mixture was ice-cooled, adjusted its pH to 5by 2N hydrochloric acid and an aqueous 10% citric acid solution, andextracted with ethyl acetate. The extract was washed with water andbrine, dried over anhydrous sodium sulfate and the solvent was removedunder reduced pressure to obtain 3.46 g of8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylic acid (the compound (2) ofthe above figure).(3) A mixture comprising 16.19 g of the compound obtained in the above(2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine and160 mL of toluene was refluxed for 2.5 hours. The reaction mixture wasice-cooled, washed with an aqueous saturated sodium hydrogencarbonatesolution, water and brine, dried over anhydrous sodium sulfate, and thesolvent was removed under reduced pressure. To a solution of theresulting compound in 100 mL of dimethylacetamide was gradually added9.55 g of potassium tert-butoxide under ice-cooling, and the mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredinto ice-water, and the precipitated crystals were collected byfiltration, washed with water and dried. To a solution of the resultingcompound in 100 mL of tetrahydrofuran was added 100 mL of an aqueoussolution containing 30.87 g of p-toluenesulfonic acid hydrate, and themixture was stirred at room temperature for 16 hours. The mixture wasdiluted with an aqueous saturated sodium hydrogencarbonate solution andextracted with ethyl acetate. The extract was washed with water andbrine, dried over anhydrous sodium sulfate, and the solvent was removedunder reduced pressure to obtain 10.41 g of4-tert-butoxycarbonylamino-4-methylcyclohexanone (the compound (3) ofthe above figure).(4) A mixture comprising 10.41 g of the compound obtained in the above(3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine and150 mL of methylene chloride was stirred at room temperature for 16hours. The mixture was diluted with an aqueous saturated sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with water and brine, dried over anhydrous sodium sulfate,and the solvent was removed under reduced pressure. To a solution of theresulting compound in 15 mL of methanol was added 3.32 g ofp-toluenesulfonic acid hydrate, followed by 160 mL of ether. Theprecipitates were collected by filtration, washed with ether and driedto obtain 7.49 g ofN-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylaminep-toluenesulfonate (the compound (4) of the above figure).(5) A mixture comprising 16.63 g of the compound obtained in the above(4), 5.0 g of 10% palladium-carbon and 400 mL of methanol was stirredunder hydrogen atmosphere (1 atm) for 24 hours. 10% palladium-carbon wasremoved by filtration and the filtrate was concentrated. The resultingresidue was dissolved in a mixture of 50 mL of an aqueous 10% sodiumhydroxide solution and 300 mL of ether, the ether layer was washed withwater and brine, dried over anhydrous sodium sulfate, and the solventwas removed under reduced pressure to obtain 6.87 g oft-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound(5) of the above figure).(6) The filtrate in the step of the above (4) was treated with anaqueous sodium hydroxide solution and extracted with chloroform. Theextract was washed with water and brine, dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas applied to NH-silica gel column chromatography (solvent:hexane-ethylacetate (30:1 to 3:1) to obtainN-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine.Then, this compound was treated in the same manner as described in theabove (5) to obtainc-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound(6) of the above figure).

Reference Example 6-2

In the same manner as in Reference Example 6-1 (1) to (5) or (6) exceptfor using benzyloxymethyl chloride instead of methyl iodide in the stepof Reference Example 6-1 (1),t-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1 -cyclohexylamine orc-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine wasobtained.

Also, in the same manner as in Reference Example 6-1 (1) to (5) or (6)except for using methoxymethyl chloride instead of methyl iodide in thestep of Reference Example 6-1 (1),t-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine orc-4-tert-butoxycarbonylamino-4-methoxymethyl-r-1-cyclohexylamine wasobtained.

Reference Examples 7-1 to 7-18

A mixture comprising 1.70 g oft-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compoundobtained in the above Reference Example 6-1 (5)), 2.04 g of2-chloropyrimidine, 3.24 mL of diisopropylethylamine and 13 mL of2-propanol was refluxed for 12 hours. After cooling, the reactionmixture was diluted with water and extracted with ethyl acetate. Theextract was washed with water and brine, dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure. The residuewas purified by silica gel column chromatography (solvent: ethylacetate-hexane (30:70 to 50:50). The resulting compound was dissolved in4 mL of dioxane, 10 mL of 4N hydrochloric acid-dioxane was addedthereto, and the mixture was stirred for 8 hours. The reaction mixturewas diluted with ether and the precipitated crystals were collected byfiltration and washed with ether. The resulting crystals were dissolvedin water, which was saturated with potassium carbonate, subsequentlyextracted with chloroform. The extract was dried over anhydrous sodiumsulfate, and the solvent was removed under reduced pressure to obtain587 mg of 1-methyl-t-4-(2-pyrimidinylamino)-r-1-cyclohexylamine(Reference Example 7-1 in Table 5).

Also, the compounds of Reference Examples 7-2 to 7-5 in Table 5 wereobtained in the same manner as mentioned above, using the correspondingstarting materials.

Also, the compounds of Reference Examples 7-6 to 7-9 in Table 5 wereobtained in the same manner as mentioned above, usingc-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compoundobtained in the above Reference Example 6-1, (6)) and the correspondingstarting materials.

Also, the compounds of Reference Examples 7-10 to 7-18 in Table 5 wereobtained in the same manner as mentioned above, using t- orc-4-tert-butoxycarbonylamino-4-hydroxymethyl-r-1-cyclohexylamine(Reference Example 6-2) and the corresponding starting materials.

Reference Examples 7-19 to 7-23

4-tert-Butoxycarbonylamino-4-methylcyclohexanone (the compound (3) ofReference Example 6-1) and the corresponding starting materials (anamine compounds) were reacted in the presence of sodiumtriacetoxyborohydride at room temperature for 16 hours under stirring,and then, an acid treatment of the reaction mixture was carried out toremove a protective group (t-butoxycarbonyl group), to obtain thecompounds of Reference Examples 7-19 to 7-23 in Table 5.

Reference Examples 8-1 to 8-4

(1) To 160 ml of a methylene chloride solution containing 16.93 g of4-(tert-butoxycarbonylamino)cyclohexanone and 0.10.55 ml ofN-methylbenzylamine was added 19.08 g of sodium triacetoxyborohydrideunder ice-cooling, and the mixture was stirred at room temperature for14 hours. The reaction mixture was diluted with an aqueous sodiumhydrogencarbonate solution and extracted with ethyl acetate. The extractwas washed with water and brine, dried over anhydrous sodium sulfate,and then, the solvent was removed under reduced pressure. The resultingresidue was suspended in hexane and collected by filtration. This motherliquor was concentrated, and the residue was purified by NH-silica gelchromatography (solvent: hexane-ethyl acetate (97:3 to 83:17), and theresidue was further suspended in hexane and collected by filtration,whereby it was combined with the product previously obtained byfiltration to give 13.55 g ofN′-benzyl-N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohxanediamine.

A suspension of 13.53 g of this compound and 2.00 g of palladiumhydroxide-carbon suspended in methanol was subjected to catalytichydrogenation under normal pressure at room temperature over 5 hours.The catalyst was removed by filtration and the filtrate was concentratedunder reduced pressure to obtain 9.93 g ofN-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine.

(2) The compound obtained in the above (1) and the correspondingstarting materials (chloride) were used and reacted under reflux in2-propanol in the presence of diisopropylethylamine for 12 hours as inReference Example 7-1, and the resulting compound was subjected to acidtreatment with hydrochloric acid, and then, neutralized with potassiumcarbonate to obtain the compounds of Reference Examples 8-1 to 8-4 inTable 5.

Reference Examples 9-1 to 9-45

2.04 g of 60% sodium hydride was gradually added to 150 ml of atetrahydrofuran solution containing 10.0 g oftrans-4-(tert-butoxycarbonylamino)cyclohexanol and 7.35 g of2-chloro-5-nitropyridine, and 30 mL of dimethylsulfoxide was furtheradded thereto, and then, the mixture was stirred at room temperature for1 day. The reaction mixture was poured into water and extracted withchloroform. The extract was washed with water and brine, dried overanhydrous sodium sulfate, and then, the solvent was removed underreduced pressure. The residue was applied to silica gel columnchromatography (solvent: chloroform alone to chloroform-ethyl acetate(20:1)). The obtained powder crystals were suspended in ethylacetate-hexane mixed solution and collected by filtration to obtain12.20 g oftrans-1-tert-butoxycarbonylamino-4-(5-nitro-2-pyridyloxy)-cyclohexane.To 10 ml of an ethanol suspension containing 800 mg of this compound wasadded 2 ml of 2N hydrochloric acid-dioxane solution, and the mixture wasstirred at room temperature for 18 hours. The precipitates werecollected by filtration to obtain 568 mg oftrans-4-(5-nitro-2-pyridyloxy)cyclohexylamine.hydrochloride (ReferenceExample 9-1 in Table 6).

Also, the compounds of Reference Examples 9-2 to 9-45 in Table 6 wereobtained in the same manner as mentioned above, using the correspondingstarting materials.

Reference Examples 9-46 to 9-47

60% sodium hydride was added to 10 ml of a tetrahydrofuran suspensioncontaining 1.00 g of trans-4-aminocyclohexanol hydrochloride and themixture was refluxed for 1 hour. After cooling to room temperature,2-chloropyrimidine was slowly added thereto and the mixture was stirredat room temperature for 6 hours. The reaction mixture was poured intoice-cold water and extracted with chloroform. The extract was washedwith brine and dried over anhydrous sodium sulfate, and then, thesolvent was removed under reduced pressure. The residue was purified byNH-silica gel column chromatography (solvent: ethyl acetate-hexane (1:4)to chloroform alone) to obtain 788 mg oftrans-4-(2-pyrimidinyloxy)cyclohexylamine (Reference Example 9-46 inTable 6).

Also, the compound of Examples 9-47 in Table 6 was obtained in the samemanner as mentioned above, using the corresponding starting materials.

Reference Example 9-48

In the same manner as in Reference Example 9-1,trans-1-tert-butoxycarbonylamino-4-(3-nitro-2-pyridyloxy)-cyclohexanewas obtained. Subsequently, a suspension of 3.35 g of this compound in30 ml of ethanol was stirred at 50° C., and 155 mg of palladium-carbon(dry) and then 1.6 ml of hydrazine monohydrate were added thereto. Afterthe mixture was stirred for 10 minutes, 185 mg of the remainingpalladium-carbon was added thereto and the mixture was refluxed for 40minutes. After the reaction mixture was cooled to room temperature, theinsolubles were removed by filtration and the filtrate was concentratedunder reduced pressure. The resulting residue was crystallized fromethanol-water (1:1) and the crystals were collected by filtration toobtain 2.58 g oftrans-1-tert-butoxycarbonylamino-4-(3-amino-2-pyridyloxy)cyclohexane.

Then, hydrochloric acid-dioxane was added to an ethanol solution of thiscompound to subject to acid treatment to obtaintrans-4-(3-amino-2-pyridyloxy)cyclohexylamine-hydrochloride (ReferenceExample 9-48 in Table 6).

Reference Example 9-49

In the same manner as in Reference Example 9-1 by usingtrans-4-(tert-butoxycarbonylamino)cyclohexanol and the correspondingstarting materials,trans-4-(5-ethoxycarbonyl-2-methylthiopyrimidin-4-yloxy)cyclohexylaminehydrochloride was obtained.

The hydrochloride compound was made into an aqueous solution, and thesolution was treated with potassium carbonate and extracted withchloroform to obtain its free form (Reference Example 9-49).

Reference Examples 9-50 to 9-54

In 50 mL of chloroform was dissolved 2.75 g ofN-tert-butoxycarbonyl-trans-4-(5-ethoxycarbonyl-2-methylthiopyrimidin-4-yloxy)cyclohexylamine(a compound of Reference Example 9-49 prior to deprotection(hydrochloric acid-dioxane treatment)), 1.73 g of 75%-m-chloroperbenzoicacid was added to the solution, and the mixture was stirred at roomtemperature for 30 minutes. Then, 1.14 g of dimethylamine hydrochlorideand 2.79 mL of triethylamine were added thereto and the mixture wasfurther stirred for 5 hours. An aqueous saturated sodiumhydrogencarbonate solution was added to the reaction mixture, and themixture was stirred. Then, the chloroform layer was collected byseparation, dried over anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The residue was purified by silica gelflash chromatography (solvent: hexane-chloroform (50:50 to 100:0)) toobtain 2.74 g ofN-tert-butoxycarbonyl-trans-4-[5-ethoxycarbonyl-2-(dimethylamino)-pyrimidin-4-yloxy]cyclohexylamine.

This compound was deprotected by treating with hydrochloricacid-dioxane, and subsequently neutralized with potassium carbonate toobtaintrans-4-[5-ethoxycarbonyl-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine(Reference Example 9-50 in Table 6).

Also, the compounds of Reference Examples 9-51 to 9-54 in Table 6 wereobtained in the same manner as mentioned above.

Reference Examples 9-55 to 9-57

(1) In 15 mL of ethanol was dissolved 2.675 g ofN-tert-butoxycarbonyl-trans-4-[5-ethoxycarbonyl-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine(the compound of Reference Example 9-50 prior to deprotectiontreatment), 3.27 mL of an aqueous 3N-sodium hydroxide solution was addedthereto at room temperature, and the mixture was stirred overnight. Thereaction mixture was diluted with water, and then, citric acid was addedthereto until the solution became neutral. The precipitated crystalswere collected by filtration, washed with water and dried under reducedpressure to obtain 2.015 g ofN-tert-butoxycarbonyl-trans-4-[5-carboxy-2-(dimethylamino)pyrimidin-4-yloxy]cyclohexylamine.(2) The compound obtained in the above (1) was used as a startingmaterial and reacted with a starting amine compound in the same manneras in Reference Example 11-1. The resulting compound (hydrochloride) wasmade into an aqueous solution, and the solution was treated withpotassium carbonate and extracted with chloroform to obtain a free form.

Thus, the compounds of Reference Examples 9-55 to 9-57 in Table 6 wereobtained.

Reference Examples 9-58 to 9-64

(1) 0.494 ml of DMSO was slowly added dropwise to 10 ml of a methylenechloride solution containing 0.526 ml of oxalyl chloride under argon gasatmosphere at −78° C. After 15 minutes from the completion of theaddition, 30 ml of a methylene chloride suspension containingtrans-4-tert-butoxycarbonylaminocyclohexanol in was added dropwise, andfurther 30 minutes later, 2.52 ml of triethylamine was added thereto andthe mixture was stirred at −78° C. for 30 minutes and at 0° C. for 15minutes. An aqueous sodium bicarbonate solution was added to thereaction mixture and the mixture was extracted with chloroform. Theextract was dried over anhydrous sodium sulfate, and then, the solventwas removed under reduced pressure. The resulting residue was suspendedin a hexane-isopropyl ether mixed solvent and collected by filtration toobtain 0.903 g of 4-(tert-butoxycarbonylamino)cyclohexanone.(2) To 350 ml of a toluene solution containing 33.05 g of the compoundobtained in the above (1) was added dropwise 313 ml of 1.0 M diisobutylaluminum hydride-toluene solution at −78° C., and the mixture wasstirred at the same temperature for 4 hours. After an excessive reagentwas decomposed by adding 33 ml of methanol dropwise to the mixture, 100ml of water was added thereto, and the mixture was stirred for 1 hour.The precipitated insolubles were removed by filtration. The organiclayer of the filtrate was separated and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, the resultingresidue was suspended in chloroform-isopropyl ether mixed solvent underheating and the insolubles were removed by filtration. The filtrate wasconcentrated, and then, the same operation was performed with isopropylether. The resulting filtrate was concentrated and the residue waspurified by silica gel flash column chromatography (solvent: ethylacetate-hexane (1:2 to 1:1)), and the obtained colorless crystals werefurther suspended in hexane-isopropyl ether mixed solvent under heatingand subjected to filtration at 0° C. to obtain 6.95 g ofcis-4-tert-butoxycarbonylaminocyclohexanol.(3) The compounds of Reference Examples 9-58 to 9-64 in Table 6 wereobtained in the same manner as in Reference Example 9-1, using theabove-obtained cis-4-tert-butoxycarbonylaminocyclohexanol and thecorresponding starting materials.

Reference Example 10-1

(1) A mixture comprising 9.13 g of4-tert-butoxycarbonylamino-4-methylcyclohexanone, 3.05 g of sodiumborohydride and 100 mL of isopropyl alcohol was stirred at roomtemperature for 1 hour. Under ice-cooling, the reaction mixture wasdiluted with an aqueous saturated ammonium chloride solution andextracted with ethyl acetate. The resulting extract was washed withwater and brine, dried over anhydrous sodium sulfate, and then, thesolvent was removed under reduced pressure to obtain 9.20 g of a mixtureof t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol andc-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol.(2) A mixture comprising 9.20 g of the compound obtained in the above(1), 8.26 g of p-methoxybenzoic acid chloride, 5.93 g ofdimethylaminopyridine and 100 mL of methylene chloride was refluxed for20 hours. After cooling, the reaction mixture was washed with an aqueoussaturated sodium hydrogencarbonate solution, an aqueous 10% citric acidsolution, water and brine, dried over anhydrous sodium sulfate, andthen, the solvent was removed. The residue was crystallized fromn-hexane to obtain 0.68 g ofc-4-tert-butoxycarbonylamino-4-methyl-O-(4-methoxyphenylcarbonyl)-r-1-cyclohexanol(cis compound).

Also, the residue was purified by silica gel column chromatography[solvent:ethyl acetate/n-hexane (1/10)] to obtain 3.50 g of a mixture(1:5) of the above compound (cis compound) andt-4-tert-butoxycarbonylamino-4-methyl-O-(4-methoxyphenylcarbonyl)-r-1-cyclohexanol(trans compound).

(3) A mixture comprising 10.68 g of the cis compound obtained in theabove (2), 6.10 g of sodium hydroxide, 150 mL of methanol and 120 mL ofwater was heated at external temperature of 75° C. for 1 hour. Aftercooling the reaction mixture, the solvent was removed under reducedpressure and extracted with ethyl acetate. The extract was washed withan aqueous saturated sodium hydrogencarbonate solution, water and brine,dried over anhydrous sodium sulfate, and then, the solvent was removedunder reduced pressure to obtain 6.61 g ofc-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol.(4) In the same manner as in the above (3) by using 3.50 g of themixture (1:5) of cis form and trans form obtained in the above (2), 1.77g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol wasobtained.

Reference Examples 10-2 to 10-8

The compounds of Reference Examples 10-2 and 10-3 in Table 6 wereobtained in the same manner as in Reference Example 9-1 by usingt-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (ReferenceExample 10-1 (4)) and the corresponding starting materials. Also, thecompounds of Reference Examples 10-4 to 10-8 in Table 6 were obtained inthe same manner as mentioned above by usingc-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexanol (ReferenceExample 10-1 (3)) and the corresponding starting materials.

Reference Examples 11-1 to 11-38 and 12-1 to 12-96

A mixture comprising 500 mg oftrans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 250 mg ofN-methyl-benzylamine, 434 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 306 mg of1-hydroxybenzotriazol and 5 ml of N,N-dimethylformamide was stirred atroom temperature for 15 hours. The reaction mixture was made basic byadding an aqueous sodium hydrogencarbonate solution, and extracted withethyl acetate. The extract was washed with water and brine, dried overanhydrous sodium sulfate, and then, the solvent was removed underreduced pressure to obtain 691 mg ofN-benzyl-trans-4-tert-butoxycarbonylamino-N-methylcyclohexanecarboxamide.A mixture comprising 670 mg of this compound, 5 mL of 4N-hydrochloricacid-dioxane and 5 ml of dioxane was stirred at room temperature for 12hours. The reaction mixture was concentrated to obtain 585 mg oftrans-4-amino-N-benzyl-N-methylcyclohexanecarboxamide hydrochloride(Reference Example 11-1 in Table 7).

Also, the compounds of Reference Examples of 11-2 to 11-38 and 12-1 to12-96 in Table 7 and Table 8 mentioned below were obtained in the samemanner as mentioned above by using the corresponding starting aminecompounds (straight chain amine compounds or cyclic secondary-aminecompounds such as a piperidine compound, a piperazine compound, etc.).(Provided that in case of free compounds, they can be obtained bysaturating an aqueous solution of a hydrochloride salt compound withpotassium carbonate, and after extracting the solution with chloroform,drying the extract over sodium sulfate and removing the solvent underreduced pressure.)

(As the starting amine compounds (a piperidine compound, a piperazinecompound, etc.), those synthesized by the methods of Reference Examples15-1 to 15-11 mentioned below, or known methods or combined methodsthereof were used.)

Reference Example 12-97

(1) A mixture comprising 4.5 g oftrans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 2.29 g ofthiomorpholine, 3.90 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,2.74 g of 1-hydroxybenzotriazol and 30 ml of N,N-dimethylformamide wasstirred at room temperature for 4 hours.

The reaction mixture was made basic by adding an aqueous sodiumhydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with water and brine, dried over anhydrous sodiumsulfate, and then, the solvent was removed under reduced pressure. Theresidue was suspended in diisopropyl ether and precipitates werecollected by filtration to obtainN-tert-butoxycarbonyl-trans-4-(4-thiomorpholinylcarbonyl)cyclohexylamine.

(2) To 50 ml of a chloroform solution containing 5.4 g of the compoundobtained in the above (1) was added 8.9 g of 75%-m-chloroperbenzoic acidunder ice-cooling, and the mixture was stirred at room temperature for 1hour. The reaction mixture was made basic by adding an aqueous sodiumhydrogencarbonate solution, and extracted with ethyl acetate. Theextract was washed with water and brine, dried over sodium sulfate, andthen, the solvent was removed under reduced pressure. The residue wassuspended in diisopropyl ether, and precipitates were collected byfiltration.

Then, this compound was suspended in 25 mL of dioxane, 4N hydrochloricacid-dioxane solution (25 mL) was added thereto, and the mixture wasstirred for 16 hours. Ether was added to the reaction mixture andprecipitates were collected by filtration and dissolved in water. Thesolution was made basic by adding potassium carbonate, and extractedwith chloroform. After the extract was dried over anhydrous sodiumsulfate, the solvent was removed under reduced pressure. The residue wassuspended in diisopropyl ether and precipitates were collected byfiltration to obtaintrans-4-(1,1-dioxo-4-thiomorpholinylcarbonyl)cyclohexylamine (ReferenceExample 12-97 in Table 8).

Reference Examples 13-1 to 13-7

To 50 ml of a methylene chloride suspension containing 5.07 g oftrans-4-(benzyloxycarbonylamino)cyclohexanecarboxylic acid were added4.0 ml of thionyl chloride and 0.3 ml of N,N-dimethylformamide and themixture was stirred at room temperature for 1 hour.

The reaction mixture was concentrated under reduced pressure and 500 mgof the residual solid was added to 8 ml of an ice-cold methylenechloride solution containing 207 mg of 2-aminopyrimidine and 0.4 ml oftriethylamine. After stirring at room temperature for 2 hours, water wasadded to the reaction mixture and the mixture was extracted withchloroform. The extract was concentrated under reduced pressure, and theresulting residue was purified by silica gel column chromatography(solvent: chloroform-methanol (50:1)) to obtain 240 mg ofN-benzyloxycarbonyl-trans-4-[(pyrimidin-2-ylamino)carbonyl]cyclohexylamine.

This compound was applied to deprotection treatment to obtaintrans-4-[(pyrimidin-2-ylamino)carbonyl]cyclohexylamine (ReferenceExample 13-1 in Table 8).

Also, the compounds of Reference Examples 13-2 to 13-7 in Table 8 wereobtained in the same manner as mentioned above by using thecorresponding starting materials instead of 2-aminopyrimidine.

The deprotection was carried out as mentioned below by using hydrogenbromide-acetic acid. That is, the compound was stirred in 3 ml of 30%hydrogen bromide-acetic acid solution at 50° C. for 4 hours. 30 ml ofdiisopropyl ether was added to the reaction mixture and precipitateswere collected by filtration to obtain a hydrobromide of the deprotectedcompound. This hydrobromide was made into a solution and the solutionwas saturated with potassium carbonate and extracted with chloroform toobtain a free form.

Provided that the deprotection of the compound of Reference Example 13-2was carried out by using palladium-carbon as mentioned below. That is,to a methanol-tetrahydrofuran suspension of the compound were added 10%palladium-carbon catalyst and ammonium formate, and the mixture wasrefluxed. The insolubles were removed by filtration and the filtrate wasconcentrated under reduced pressure.

Reference Examples 13-8 to 13-16

Under argon atmosphere, a mixture comprising 1.0 gtrans-4-(benzyloxycarbonylamino)cyclohexanecarbonyl chloride, 1.92 g oftributylphenyltin, 61 mg of dichlorobis-(triphenylphosphine)palladiumand 10 mL of dioxane was stirred at 110° C. for 12 hours. After cooling,the reaction mixture was concentrated by a centrifugal concentrator, andthen, the residue was dissolved in tetrahydrofuran and evaporated todryness with 5 g of silica gel. The resulting residue was purified bysilica gel flash chromatography (solvent: ethyl acetate-hexane (1:2) to(1:1) to obtain 883 mg ofN-benzyloxycarbonyl-trans-4-benzoylcylohexylamine.

870 mg of this compound was stirred with 1.0 g of trimethylsilyl iodideand 5 mL of chloroform under argon atmosphere at room temperature for 2hours. Disappearance of the starting material was confirmed by TLC, 0.17mL of methanol and 5 mL of diethyl ether were added to the reactionmixture and the mixture was stirred at room temperature for 3 days. Theresulting precipitates were collected by filtration, washed withanhydrous diethyl ether, and dried to obtain 830 mg oftrans-4-benzoylcyclohexylamine (Reference Example 13-8 in Table 8).

Also, the compounds of Reference Examples 13-9 to 13-16 in Table 8 wereobtained in the same manner as mentioned above.

Reference Example 13-17

(1) trans-4-Methoxycarbonylcyclohexane-1-carbonyl chloride was obtainedfrom 5 g of trans-4-methoxycarbonylcyclohxane-1-carboxylic acid andoxalyl chloride. 7.58 g of morpholine was added dropwise to 50 mL of amethylene chloride solution thereof under ice-cooling, and the mixturewas stirred for 2 hours. The reaction mixture was poured into an aqueous10% citric acid solution, extracted with chloroform, dried overanhydrous magnesium sulfate, and then, the solvent was removed underreduced pressure. The residue was purified by silica gel flash columnchromatography (solvent: ethyl acetate-hexane (1:1) to ethylacetate-chloroform (1:1)) and crystallized from hexane to obtain 6.49 gof trans-1-methoxycarbonyl-4-(morpholinocarbonyl)cyclohexane.(2) Under argon atmosphere, 10 mL of a tetrahydrofuran solutioncontaining 2.0 g of the compound obtained in the above (1) was addeddropwise to 40 mL of a hexane-tetrahydrofuran (3:5) solution containingLDA (lithium diisopropylamide) (0.024 mol) prepared at the time of usingat −78° C. and the temperature of the mixture was elevated to −30° C.over 2 hours, while stirring. The reaction mixture was cooled again to−78° C., reacted with 1.46 mL of methyl iodide, and allowed to stand to0° C., and then, water was added thereto and the mixture was extractedwith ethyl acetate. The extract was successively washed with an aqueous10% citric acid solution, water and brine, dried over anhydrous sodiumsulfate, and then, the solvent was removed under reduced pressure. Theresidue was purified by silica gel flash column chromatography (solvent:ethyl acetate-hexane (1:2) to (1:1)) to obtain 1.47 g of isomericmixture of 1-methoxycarbonyl-1-methyl-4-(morpholinocarbonyl)cyclohexane.This mixture was stirred in a mixture comprising 158 mg of sodiumhydroxide, 1 mL of ethanol and 1 mL of water at room temperature for 12hours. The reaction mixture was extracted with diethyl ether, theextract was washed with water, dried over anhydrous sodium sulfate, andthen, the solvent was removed under reduced pressure. The residue wasrecrystallized from a mixed solvent comprising diethyl ether-hexane toobtain 592 mg of single isomer of1-methoxycarbonyl-1-methyl-4-(morpholinecarbonyl)cyclohexane.(3) 546 mg of the compound (single isomer) obtained in the above (2) wasstirred in a mixture comprising 251 mg of sodium hydroxide, 5 mL ofmethanol and 10 mL of water at 110° C. for 2 hours. After cooling, pH ofthe reaction mixture was adjusted to 3 by 10% hydrochloric acid,extracted three times with chloroform, the extract was dried overanhydrous magnesium sulfate, and then, the solvent was removed underreduced pressure. 5 mL of a toluene solution containing 479 mg of theresulting compound (carboxylic acid), 550 mg of diphenylphosphoryl azideand 216 mg of benzyl alcohol was stirred under heating for 12 hours.After cooling, an aqueous 10% citric acid solution was added to thereaction mixture, and the toluene layer was separated, washed with brineand dried over anhydrous sodium sulfate, and then, the solvent wasremoved under reduced pressure. The resulting residue was purified bysilica gel flash chromatography (solvent: ethyl acetate-hexane (1:2)) to(1:1) to obtain 387 mg ofN-benzyloxycarbonyl-1-methyl-4-(morpholinocarbonyl)cyclohexylamine.

This compound was deprotected by treating with trimethylsilyl iodide toobtain 1-methyl-4-(morpholinocarbonyl)cyclohexylamine (Reference Example13-17 in Table 8).

Reference Examples 13-18 to 13-21

N-tert-butoxycarobonyl-trans-4-(1-piperazinylcarbonyl)cyclohexylaminewas obtained by treatingtrans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid andpiperazine in the same manner as in the above-mentioned ReferenceExample 11-1.

Methyl chlorocarbonate was added dropwise to a mixture comprising 400 mgof this compound, 260 mg of triethylamine and 8 mL of methylenechloride-under ice-cooling, and the mixture was stirred at roomtemperature overnight. The reaction mixture was successively washed withwater and brine, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure. The resulting residue was suspended indiisopropyl ether and precipitates were collected by filtration toobtain 410 mgN-tert-butoxycarbonyl-trans-4-(4-methoxycarbonyl-1-piperazinylcarbonyl)cyclohexylamine.

This compound was deprotected under acidic conditions according to theconventional method and the acidic mixture was returned to basic toobtain trans-4-(4-methoxycarbonyl-1-piperazinylcarbonyl)cyclohexylamine(Reference Example 13-18 of Table 8).

Also, the compounds of Reference Examples 13-19 to 13-21 in Table 8 wereobtained in the same manner as mentioned above.

Reference Example 13-22

A mixture comprising 623 mg ofN-tert-butoxycarbonyl-trans-4-(piperazinocarbonyl)cyclohexylamine, 340mg of 3,4-diethoxy-3-cyclobuten-1,2-dione and 5 ml of ethanol wasstirred at room temperature for 2.5 days. The reaction mixture wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (solvent:chloroform-methanol (50:1)) and subsequently triturated with ether.

This compound was deprotected by treating with hydrochloric acid-dioxaneto obtaintrans-4-[4-(4-ethoxy-1,2-dioxo-3-cyclobuten-3-yl)piperazinylcarbonyl]cyclohexylamine(Reference Example 13-22 in Table 8).

Reference Example 13-23

(1) A mixture comprising 1101 mg of N-benzyloxycarbonylpiperazine, 1131mg of 3,4-dibutoxy-3-cyclobutene-1,2-dione and 5 ml of ethanol wasstirred at room temperature for 25 hours. The reaction mixture wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel column chromatography (solvent: chloroform-ethylacetate (19:1)) to obtain 1570 mg of1-benzyloxycarbonyl-4-(4-butoxy-1,2-dioxo-3-cyclobuten-3-yl)-piperazine.

This compound was deprotected by treating with palladium-carbon in thepresence of 3 ml of 10% hydrochloric acid under hydrogen atmosphere toobtain 4-(4-butoxy-1,2-dioxo-3-cyclobuten-3-yl)-piperazine.

(2) The compound obtained in the above (1) was reacted withtrans-(4-benzyloxycarbonylamino)cyclohexanecarbonyl chloride inmethylene chloride in the presence of triethylamine to obtainN-benzyloxycarbonyl-trans-4-[4-(4-butoxy-1,2-dioxo-3-cyclobuten-3-yl)piperazinocarbonyl]cyclohexylamine.(3) The compound obtained in the above (2) and dimethylaminehydrochloride were reacted in ethanol in the presence of triethylamineto obtainN-benzyloxycarbonyl-trans-4-[4-(4-dimethylamino-1,2-dioxo-3-cyclobuten-3-yl)piperazinylcarbonyl]cyclohexylamine.This compound was deprotected by treating with trimethylsilyl iodide toobtaintrans-4-[4-(4-dimethylamino-1,2-dioxo-3-cyclobuten-3-yl)piperazinylcarbonyl]cyclohexylamine(Reference Example 13-23 in Table 8).

Reference Example 13-24

0.15 ml of triethylamine and 0.07 ml of methanesulfonyl chloride wereadded to 10 ml of a tetrahydrofuranmethylene chloride suspensioncontaining 0.31 g ofN-benzyloxycarbonyl-trans-4-[(5-hydroxylmethyl-2-isoindolinyl)carbonyl]cyclohexylamineunder ice-cooling, and the mixture was stirred under ice-cooling for 1hour. Water was added to the reaction mixture and the mixture wasextracted with ethyl acetate. After the extract was dried over sodiumsulfate, the solvent was removed under reduced pressure. To the residuewere added 5 ml of dimethylformamide and 0.25 ml of morpholine, and themixture was stirred at room temperature overnight. Water was added tothe reaction mixture and the mixture was extracted with ethyl acetate.After the extract was dried over anhydrous sodium sulfate, the solventwas removed under reduced pressure. The residue was purified by silicagel chromatography (solvent: chloroform-methanol=100:1). This compoundwas treated with palladium-carbon under hydrogen atmosphere to obtaintrans-4-[(5-morpholinomethyl-2-isoindolinyl)carbonyl]cyclohexylamine(Reference Example 13-24 in Table 8).

Reference Examples 13-25 to 13-29

(1) 20 g of manganese dioxide was added to 120 ml of a chloroformsolution containing 4.0 g ofN-benzyloxycarbonyl-trans-4-[(5-hydroxymethyl-2-isoindolinyl)carbonyl]cyclohexylamine,and the mixture was stirred at room temperature for 4 hours. Manganesedioxide was removed by filtration through Celite and the solvent wasremoved under reduced pressure. The residue was suspended inhexane-ethyl acetate and the crystals were collected by filtration toobtainN-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl)carbonyl]cyclohexylamine.(2) To an aqueous solution containing 3.35 g of silver nitrate wereadded 2.75 g of the compound obtained in the above (1) and 110 ml ofethanol under ice-cooling, and then, an aqueous solution containing 2.61g of potassium hydroxide was added dropwise thereto. The mixture wasstirred under ice-cooling for 1 hour and separated by filtration throughCelite, and then, the solvent was removed under reduced pressure. To theresidue was added 50 ml of an aqueous 1N hydrochloric acid solution andthe mixture was extracted with chloroform. After the extract was driedover anhydrous sodium sulfate, the solvent was removed under reducedpressure. The residue was suspended in hexane-ether and the crystalswere collected by filtration to obtainN-benzyloxycarbonyl-trans-4-[(5-carboxy-2-isoindolinyl)carbonyl]cyclohexylamine.(3) The compound obtained in the above (2) was used and condensed with astarting amine compound in the same manner as in Reference Example 11-1,and subsequently treated with palladium-carbon under hydrogen atmosphereto obtaintrans-4-[(5-dimethylaminocarbonyl-2-isoindolinyl)carbonyl]cyclohexylamine(Reference 13-25 in Table 8).

Also, the compounds of Reference Examples 13-26 to 13-29 in Table 8 wereobtained in the same manner as mentioned above.

Reference Examples 13-30 to 13-33

(1) 2.6 g of tert-butylcarbamate, 3.5 ml of triethylsilane and 1.15 mlof trifluoroacetic acid were added to 25 ml of an acetonitrilesuspension containing 3.0 g ofN-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl)carbonyl]cyclohexylamine(the compound obtained in Reference Example 13-25 (1)), and the mixturewas stirred at room temperature overnight. Water was added to thereaction mixture and the mixture was extracted with chloroform. Afterthe extract was dried over anhydrous sodium sulfate, the solvent wasremoved under reduced pressure. The residue was suspended inhexane-ethyl acetate and the crystals were collected by filtration toobtainN-benzyloxycarbonyl-trans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl)carbonyl]cyclohexylamine.

(2) The compound obtained in the above (1) was treated withpalladium-carbon under hydrogen atmosphere to obtaintrans-4-[(5-tert-butoxycarbonylaminomethyl-2-isoindolinyl)carbonyl]cyclohexylamine(Reference Example 13-30 in Table 8).

(3) The compound obtained in the above (1) was treated with 4Nhydrochloric acid-dioxane to obtainN-benzyloxycarbonyl-trans-4-[(5-aminomethyl-2-isoindolinyl)carbonyl]cyclohexylaminehydrochloride.

(4) 0.25 ml of cyclopropanecarbonyl chloride was added to 5 ml of amethylene chloride-pyridine solution containing 0.5 g of the compound(hydrochloride) obtained in the above (3), and the mixture was stirredat room temperature for 4 hours. Diluted aqueous hydrochloric acidsolution was added to the reaction mixture and the mixture was extractedwith chloroform. After the extract was dried over anhydrous sodiumsulfate, the solvent was removed under reduced pressure. The residue waspurified by silica gel chromatography (solvent:chloroform-methanol=50:1) to obtain crystals. This compound was treatedwith palladium-carbon under hydrogen atmosphere to obtaintrans-4-[(5-cyclopropylcarbonylaminomethyl-2-isoindolinyl)carbonyl]cyclohexylamine(Reference Example 13-31 in Table 8).

Also, the compounds of Reference Examples 13-32 to 13-33 in Table 8 wereobtained in the same manner as mentioned above.

Reference Example 13-34

(1) 0.08 g of hydroxylamine hydrochloride and 0.09 g of sodium formatewere added to 3 ml of a formic acid solution containing 0.3 g ofN-benzyloxycarbonyl-trans-4-[(5-formyl-2-isoindolinyl)carbonyl]cyclohexylamine(the compound obtained in Reference Example 13-25 (1)), and the mixturewas refluxed for 3 hours. Water was added to the reaction mixture andthe mixture was extracted with ethyl acetate. After the extract wasdried over anhydrous sodium sulfate, the solvent was removed underreduced pressure. The residue was purified by NH silica gelchromatography (solvent:chloroform-ethyl acetate=50:1), and theresulting compound was treated with trimethylsilyl iodide to obtaintrans-4-[(5-cyano-2-isoindolinyl)carbonyl]cyclohexylamine hydroiodide(Reference Example 13-34 in Table 8).

Reference Examples 13-35 to 13-46

(1) 17.33 g of stannous chloride was added to a hydrated ethanol (120 mlof ethanol+1.2 ml of water) suspension containing 6.08 g ofN-benzyloxycarbonyl-trans-4-[(6-nitro-1-indolinyl)carbonyl]cyclohexylamine(the compound obtained in the same manner as in Reference Example 13-1before deprotection), and the mixture was refluxed under argonatmosphere for 4.5 hours. An aqueous 10% sodium hydroxide solution wasadded to the reaction mixture to adjust pH of the mixture to pH 9 to 10,the mixture was diluted with 300 ml of chloroform and dried overanhydrous magnesium sulfate, and then, the insolubles were removed byfiltration. The filtrate was concentrated under reduced pressure, andthe resulting residue was purified by silica gel column chromatography(solvent: chloroform-ethyl acetate (2:1)) to obtain 4.72 g ofN-benzyloxycarbonyl-trans-4-[(6-amino-1-indolinyl)carbonyl]cyclohexylamine.(2) 0.12 ml of pyridine and 0.104 ml of acetic anhydride were added to10 ml of a methylene chloride solution containing 396 mg of the compoundobtained in the above (1), and the mixture was stirred for 5 hours. 5%hydrochloric acid was added to the reaction mixture and the mixture wasextracted with chloroform. The extracted layer was successively washedwith water and an aqueous saturated sodium bicarbonate solution anddried over anhydrous sodium sulfate, and then, the solvent was removedunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: chloroform-ethyl acetate (1:1)).

This compound was deprotected by treating with palladium-carbon toobtain trans-4-[(6-acetylamino-1-indolinyl)carbonyl]cyclohexylamine(Reference Example 13-35 in Table 8).

Also, the compounds of Reference Examples 13-36 to 13-37 in Table 8 wereobtained in the same manner as mentioned above.

(3) 0.085 ml of methanesulfonyl chloride was added to 10 ml of apyridine solution containing 400 mg of the compound obtained in theabove (1) at room temperature, and the mixture was stirred for 5 hours.The reaction mixture was concentrated under reduced pressure, theresidue was dissolved in chloroform, washed successively with 5%hydrochloric acid, water and an aqueous saturated sodium bicarbonatesolution and dried over anhydrous sodium sulfate, and then, the solventwas removed under reduced pressure. The residue was purified by silicagel column chromatography (solvent: chloroform-ethyl acetate (2:1)).

This compound was deprotected by treating with palladium-carbon toobtaintrans-4-[(6-methylsulfonylamino-1-indolinyl)carbonyl]cyclohexylamine(Reference Example 13-38 in Table 8).

(4) 15 ml of N,N-dimethylformamide solution containing 403 mg of thecompound obtained in the above (1), 169 mg of N,N-dimethylglycinehydrochloride, 243 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, 173 mg of 1-hydroxybenzotriazole and 0.181 ml oftriethylamine in was stirred at room temperature for 5 hours. Thereaction mixture was concentrated under reduced pressure, the residuewas dissolved in ethyl acetate, successively washed with an aqueoussaturated sodium bicarbonate solution, water and brine, dried overanhydrous sodium sulfate, and then, the solvent was removed underreduced pressure. The residue was purified by silica gel columnchromatography (solvent:chloroform-methanol (50:1)).

This compound was deprotected by treating with palladium-carbon toobtaintrans-4-{[6-(dimethylamino)methylcarbonyl-1-indolinyl]carbonyl}cyclohexylamine(Reference Example 13-39 in Table 8).

(5) 0.8 ml of an aqueous 37% formalin solution and 635 mg of sodiumtriacetoxyborohydride were added to 10 ml of an acetonitrile suspensioncontaining 402 mg of the compound obtained in the above (1) at roomtemperature, and the mixture was stirred for 1.5 hours. The reactionmixture was diluted with water and extracted with ethyl acetate. Theextracted layer was washed with water and brine in order, dried overanhydrous sodium sulfate, and then, the solvent was-removed underreduced pressure. The residue was purified by silica gel columnchromatography (solvent:chloroform-ethyl acetate (2:1)).

This compound was deprotected by treating with palladium-carbon toobtain trans-4-[(6-dimethylamino-1-indolinyl)carbonyl]cyclohexylamine(Reference Example 13-40 in Table 8).

(6) The compounds of Reference Examples 13-41 to 13-46 were obtained inthe same manner as in the above (1) to (5) except for usingN-benzyloxycarbonyl-trans-4-[(5-nitro-1-indolinyl)carbonyl]cyclohexylamine(the compound obtained in the same manner as in Reference Example 13-1)as a starting material.

Reference Examples 13-47 to 13-52

451 mg of potassium carbonate and 238 mg of 2-(dimethylamino)ethylchloride hydrochloride were added to 5 ml of a N,N-dimethylformamidesolution containing 400 mg ofN-benzyloxycarbonyl-trans-4-[(5-hydroxy-1-indolinyl)carbonyl]cyclohexylamine(the compound obtained in the same manner as in Reference Example 13-1),and the mixture was stirred at 50° C. for 19 hours. The reaction mixturewas concentrated under reduced pressure, and a solution of the residuein chloroform was washed with water, dried over sodium sulfate, andthen, the solvent was removed under reduced pressure. The residue waspurified by silica gel column chromatography (solvent:chloroform-methanol (30:1)).

100 mg of 10% palladium-carbon catalyst and 920 mg of ammonium formatewere added to 10 ml of methanol-10 ml of tetrahydrofuran suspensioncontaining this compound, and the mixture was refluxed for 17 hours. Theinsolubles were removed by filtration, and the filtrate was concentratedunder reduced pressure to obtain 281 mg oftrans-4-{[5-(2-dimethylaminoethyl)oxy-1-indolinyl]carbonyl}cyclohexylamine(Reference Example 13-47 in Table 8).

Also, the compounds of Reference Examples 13-48 to 13-52 in Table 8 wereobtained in the same manner as mentioned above.

Reference Examples 14-1 to 14-16

A mixture comprising 400 mg ofcis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 216 mg of4-hydroxypiperidine, 244 mg of 1-hydroxybenzotriazole, 686 mg ofO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumhexaflubrophosphate, 398μl of N-methylmorpholine and 11 ml of N,N-dimethylformamide was stirredat room temperature for 14 hours. Water was added to the reactionmixture and the mixture was extracted with ethyl acetate. The extractwas washed with an aqueous 10% citric acid solution, water and brine,dried over anhydrous sodium sulfate, and then, the solvent was removedunder reduced pressure. The resulting residue was dissolved in 5 ml ofdioxane, then, 6 ml of 4N hydrochloric acid-dioxane was added thereto,and the mixture was stirred at room temperature for 12 hours. Thereaction mixture was concentrated, methanol was added to the residue andthe mixture was concentrated under reduced pressure. Next, ether wasadded to the residue, and the mixture was concentrated under reducedpressure to obtaincis-4-(4-hydroxypiperidinocarbonyl)cyclohexylamine•hydrochloride(Reference Example 14-1 in Table 8).

Also, the compounds of Examples 14-2 to 14-16 in Table 8 were obtainedin the same manner as mentioned above, sing the corresponding startingmaterials. (Provided that in case of free compounds, they can beobtained by saturating an aqueous solution of a hydrochloride saltcompound with potassium carbonate, and after extracting the solutionwith chloroform, drying the extract over anhydrous sodium sulfate andremoving the solvent under reduced pressure.)

Reference Example 15-1

To a dimethylformamide (7 ml) solution containingN-(tert-butoxycarbonyl)piperazine (1.0 g) were added potassium carbonate(742 mg) and then butyl iodide (1.09 g), and the mixture was stirred atroom temperature for 15 hours to undergo reaction, thereby obtainingN-tert-butoxycarbonyl-N-butylpiperazine. This compound was acid-treatedwith hydrochloric acid to obtain N-butylpiperazine•dihydrochloride.

Also, N-isopropylpiperazine•dihydrochloride was obtained in the samemanner as mentioned above.

Reference Example 15-2

Dimethylamine hydrochloride (430 mg) was added to a methylene chloride(10 ml) solution containing 4-(tert-butoxycarbonyl)piperidone (1.0 g),and under ice-cooling, triethylamine (0.84 ml) and triacetoxyborohydride(1.17 g) were further added thereto, and the mixture was stirred at roomtemperature for 3 hours to undergo reaction, thereby obtainingN-tert-butoxycarbonyl-4-dimethylaminopiperidine. This compound wasacid-treated with hydrochloric acid to obtain4-(dimethylamino)piperidine-dihydrochloride.

Reference Example 15-3

Sodium triacetoxyborohydride (10.51 g) was added to a methylene chloride(50 ml) solution containing N-formylpiperazine (5.08 g) andcyclohexanecarboxyaldehyde (7.50 g) under ice-cooling, and the mixturewas stirred at room temperature for 18 hours to undergo reaction,thereby obtaining 1-formyl-4-cyclohexylmethylpiperazine, which was thenacid-treated with hydrochloric acid to obtain1-(cyclohexylmethyl)piperazine-hydrochloride.

Reference Example 15-4

60% Sodium hydride (0.232 g) was gradually added to a tetrahydrofuran(4.5 ml) solution containing 1-tert-butoxycarbonyl-4-hydroxypiperidine(0.900 g) and 2-chloropyrimidine (0.666 g), and 2 hours later, dimethylsulfoxide (1.0 ml) was added thereto, and the mixture was stirred atroom temperature for 1 day to undergo reaction, thereby obtaining1-tert-butoxycarbonyl-4-(2-pyrimidinyloxy)piperidine. This compound wasacid-treated with hydrochloric acid to obtain4-(2-pyrimidinyloxy)piperidine•hydrochloride.

Also, the following compounds were obtained in the same manner asmentioned above. 4-(5-Cyano-2-pyridyloxy)piperidine•hydrochloride4-(5-Bromo-2-pyrimidinyloxy)piperidine•hydrochloride4-(p-Nitrophenoxy)piperidine-hydrochloride

Reference Example 0.15-5

A mixture comprising N-(tert-butoxycarbonyl)piperidine-4-carboxylic acid(700 mg), morpholine (319 μL),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (702 mg),1-hydroxybenzotriazole (495 mg) and N,N-dimethylformamide (9 ml) wasstirred at room temperature for 16 hours to undergo reaction, and theresulting compound was acid-treated with hydrochloric acid to obtain4-(morpholinocarbonyl)piperidine•hydrochloride.

Also, the following compounds were obtained in the same manner asmentioned above.

-   4-(Diethylaminocarbonyl)piperidine•hydrochloride-   4-(N-methyl-N-benzylaminocarbonyl)piperidine•hydrochloride-   4-(p-Chlorophenylaminocarbonyl)piperidine-hydrochloride

Reference Example 15-6

A mixture comprising 4-amino-1-(tert-butoxycarbonyl)piperidine (700 mg),benzoic acid (512 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide(804 mg), 1-hydroxybenzotriazole (567 mg) and N,N-dimethylformamide (10ml) was stirred at room temperature for 16 hours to undergo reaction,and the resulting compound was acid-treated with hydrochloric acid toobtain 4-(benzoylamino)piperidine•hydrochloride.

Also, the following compounds were obtained in the same manner asmentioned above.

-   4-(2-Pyridylcarbonylamino)piperidine•hydrochloride-   4-(Cyclohexylcarbonylamino)piperidine•hydrochloride

Reference Example 15-7

An acetonitrile (7 ml) solution containingN-(tert-butoxycarbonyl)piperazine (700 mg), N-methyl-N-phenylcarbamoylchloride (700 mg) and triethylamine (1.05 mL) was stirred at roomtemperature for 15 hours to undergo reaction, and the resulting compoundwas acid-treated with hydrochloric acid to obtain1-(N-methyl-N-phenylaminocarbonyl)piperazine hydrochloride.

Reference Example 15-8

Methanesulfonyl chloride (3.65 ml) was added to a methylene chloride (50ml) solution containing N-formylpiperazine (5.08 g) and triethylamine(6.85 ml) under ice-cooling, and the mixture was stirred at roomtemperature for 18 hours to undergo reaction, thereby obtaining1-formyl-4-methanesulfonylpiperazine. This compound was acid-treatedwith hydrochloric acid to obtain1-methanesulfonylpiperazine•hydrochloride. Also,1-(phenylsulfonyl)piperazine•hydrochloride was obtained in the samemanner as mentioned above by using the corresponding starting material.

Reference Example 15-9

0.84 ml of triethylamine and 0.37 ml of methanesulfonyl chloride wereadded to 10 ml of a tetrahydrofuran solution containing 0.99 g of2-tert-butoxycarbonyl-5-(hydroxylmethyl)isoindoline under ice-cooling,and the mixture was stirred under ice-cooling for 1 hour. Water wasadded to the reaction mixture and the mixture was extracted with ethylacetate. After the extract was dried over sodium sulfate, the solventwas removed under reduced pressure. To the residue were added 20 ml ofethanol and 1.02 ml of diisopropylethylamine, and the mixture wasrefluxed for 30 minutes. The reaction mixture was concentrated underreduced pressure, and ethyl acetate and an aqueous 5% hydrochloric acidsolution were added to the residue, followed by the extraction. Afterthe extract was dried over sodium sulfate, the solvent was removed underreduced pressure. The residue was purified by silica gel chromatography(solvent: hexane-ethyl acetate=4:1) to obtain an oily product. This oilyproduct was dissolved in 5 ml of dioxane, then, 8 ml of 4N hydrochloricacid-dioxane was added thereto, and the mixture was stirred at roomtemperature. The precipitates precipitated by addition of 20 ml of etherwere collected by filtration and washed with ether to obtain5-(ethoxymethyl)isoindoline-hydrochloride.

Also, the following compounds were obtained in the same manner asmentioned above.

-   5-(Methoxymethyl)isoindoline•hydrochloride-   5-(Isopropyloxymethyl)isoindoline•hydrochloride

Reference Example 15-10

0.85 ml of triethylamine and 0.35 ml of methyl chloroformate were addedto 8 ml of a methylene chloride solution containing 0.72 g of5-amino-2-tert-butoxycarbonylisoindoline, and the mixture was stirred atroom temperature for 5 hours. Water was added to the reaction mixtureand the mixture was extracted with ethyl acetate. After the extract wasdried over anhydrous sodium sulfate, the solvent was removed underreduced pressure. The residue was purified by silica gel chromatography(solvent:chloroform-ethyl acetate=2:1) to obtain an oil. This oil wasdissolved in 5 ml of dioxane, then, 8 ml of 4N hydrochloric acid-dioxanewas added thereto, and the mixture was stirred at room temperature. Theprecipitates precipitated by addition of 20 ml of ether were collectedby filtration and washed with ether to obtain5-(methoxycarbonylamino)isoindoline.hydrochloride.

Also, the following compounds were obtained in the same manner asmentioned above. 5-(Acetylamino)isoindoline•hydrochloride

Reference Example 15-11

2-tert-Butoxycarbonyl-5-aminoisoindoline (the compound obtained in thesame manner as in WO 00/23428) and dimethylglycine were used as startingmaterials and reacted in the same manner as in Reference Example 11-1 toobtain 5-(dimethylaminomethylcarbonylamino)isoindoline.

In the following Table 1a to Table 1d and Table 2 to Table 8, chemicalstructures and physical properties of the compounds of the aboveExamples and Reference Examples are shown. (In Tables, “Me” represents amethyl group. Also, in Tables, MS APCI (m/z) represents massspectrometric value (atmospheric pressure chemical ionization massspectrum).)

TABLE 1a

Exam- ple Physical properties, No. R²—X— R¹ Salt etc. 1a-1

H 2HCl Colorless powderMS · APCI (m/z): 373[M + H]+ 1a-2

H 2HCl Brownish powderMS · APCI (m/z): 328[M + H]+ 1a-3

H HCl Colorless powderMS · APCI (m/z): 353[M + H]+ 1a-4

H 2HCl Colorless powderMS · APCI (m/z): 396[M + H]+ 1a-5

H 2HCl Colorless powderMS · APCI (m/z): 353[M + H]+ 1a-6

H 2HCl Yellowish powderMS · APCI (m/z): 373[M + H]+ 1a-7

H 2HCl Colorless powderMS · APCI (m/z): 329[M + H]+ 1a-8

H 2HCl Colorless powderMS · APCI (m/z): 407,409 [M + H]+ 1a-9

H 2HCl Pale yellowish powderMS · APCI (m/z): 375[M + H]+ 1a-10

H 2HCl Colorless powderMS · APCI (m/z): 363[M + H]+ 1a-11

H 2HCl Colorless powderMS · APCI (m/z): 329[M + H]+ 1a-12

H HCl Pale brownish powderMS · APCI (m/z): 334[M + H]+ 1a-13

H HCl Colorless powderMS · APCI (m/z): 372[M + H] 1a-14

H HCl Colorless powderMS · APCI (m/z): 440[M + H] 1a-15

H HCl Colorless powderMS · APCI (m/z): 402[M + H] 1a-16

H 2HCl Purified powderMS · APCI (m/z): 364, 362 1a-17

H 2HCl Purified powderMS · APCI (m/z): 364, 362 1a-18

H 2HCl Purified powderMS · APCI (m/z): 364, 362 1a-19

H 2HCl Purified powderMS · APCI (m/z): 365, 363 1a-20

H 2HCl Purified powderMS · APCI (m/z): 397 1a-21

H 2HCl Purified powderMS · APCI (m/z): 357 1a-22

H 2HCl Purified powderMS · APCI (m/z): 354 1a-23

H 2HCl Purified powderMS · APCI (m/z): 354 1a-24

H 2HCl Colorless powderMS · APCI (m/z): 378[M + H]+ 1a-25

H 2HCl Purified powderMS · APCI (m/z): 329 1a-26

H HCl Brownish powderMS · APCI (m/z): 389[M + H] 1a-27

H 2HCl Colorless powderMS · APCI (m/z): 375[M + H]+ 1a-28

H 2HCl Colorless powderMS · APCI (m/z): 447[M + H]+ 1a-29

H 2HCl Colorless powderMS · APCI (m/z): 448[M + H]+ 1a-30

H 2HCl Colorless powderMS · APCI (m/z): 477[M + H]+ 1a-31

H 2HCl Colorless powderMS · APCI (m/z): 483[M + H]+ 1a-32

H 2HCl Colorless powderMS · APCI (m/z): 486[M + H]+ 1a-33

H 2HCl Colorless powderMS · APCI (m/z): 444[M + H]+ 1a-34

H 2HCl Colorless powderMS · APCI (m/z): 470[M + H]+ 1a-35

H 2HCl Colorless powderMS · APCI (m/z): 485[M + H]+ 1a-36

H 2HCl Colorless powderMS · APCI (m/z): 511[M + H]+ 1a-37

H 2HCl Colorless powderMS · APCI (m/z): 485[M + H]+ 1a-38

H 2HCl Colorless powderMS · APCI (m/z): 488[M + H]+ 1a-39

H 2HCl Colorless powderMS · APCI (m/z): 472[M + H]+ 1a-40

H 2HCl Colorless powderMS · APCI (m/z): 446[M + H]+ 1a-41

H 2HCl Colorless powderMS · APCI (m/z): 518[M + H]+ 1a-42

H 2HCl Purified powderMS · APCI (m/z): 405 1a-43

H 2HCl Colorless powderMS · APCI (m/z): 395[M + H]+ 1a-44

H 2HCl Purified powderMS · APCI (m/z): 386 1a-45

H 2HCl Purified powderMS · APCI (m/z): 372 1a-46

H 2HCl Purified powderMS · APCI (m/z): 370 1a-47

H 2HCl Purified powderMS · APCI (m/z): 370 1a-48

H 2HCl Purified powderMS · APCI (m/z): 420 1a-49

H 3HCl Purified powderMS · APCI (m/z): 367 1a-50

H 2HCl Purified powderMS · APCI (m/z): 370 1a-51

H 2HCl Colorless powderMS · APCI (m/z): 352[M + H] 1a-52

H 2HCl Colorless powderMS · APCI (m/z): 370[M + H] 1a-53

H 2HCl Colorless powderMS · APCI (m/z): 432,430 [M + H] 1a-54

H 2HCl Colorless powderMS · APCI (m/z): 382[M + H] 1a-55

H 2HCl Colorless powderMS · APCI (m/z): 384[M + H]+ 1a-56

H 2HCl Colorless powderMS · APCI (m/z): 368[M + H]+ 1a-57

H 2HCl Colorless powderMS · APCI (m/z): 413[M + H]+ 1a-58

H 2HCl Colorless powderMS · APCI (m/z): 419[M + H]+ 1a-59

H 2HCl Colorless powderMS · APCI (m/z): 453[M + H]+ 1a-60

H 2HCl Colorless powderMS · APCI (m/z): 373[M + H]+ 1a-61

H 2HCl Colorless powderMS · APCI (m/z): 353[M + H]+ 1a-62

H 2HCl Pale yellowish powderMS · APCI (m/z): 353[M + H]+ 1a-63

H 2HCl Pale brownish powderMS · APCI (m/z): 373[M + H]+ 1a-64

H 2HCl Colorless powderMS · APCI (m/z): 329[M + H]+ 1a-65

H 2HCl Pale yellowish powderMS · APCI (m/z): 409[M + H]+ 1a-66

H 2HCl Pale yellowish powderMS · APCI (m/z): 375[M + H]+ 1a-67

Me 2HCl Colorless powderMS · APCI (m/z): 343[M + H]+ 1a-68

Me 2HCl Pale yellowish powderMS · APCI (m/z): 387[M + H]+ 1a-69

Me 2HCl Yellowish powderMS · APCI (m/z): 387[M + H]+ 1a-70

Me 2HCl Colorless powderMS · APCI (m/z): 367[M + H]+ 1a-71

Me 2HCl Colorless powderMS · APCI (m/z): 367[M + H]+ 1a-72

Me 2HCl Brownish powderMS · APCI (m/z): 343[M + H]+ 1a-73

Me 2HCl Pale yellowish powderMS · APCI (m/z): 387[M + H]+ 1a-74

Me 2HCl Yellowish powderMS · APCI (m/z): 387[M + H]+ 1a-75

Me 2HCl Colorless powderMS · APCI (m/z): 367[M + H]+ 1a-76

Me 2HCl Colorless powderMS · APCI (m/z): 367[M + H]+ 1a-77

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 405[M + H]+ 1a-78

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 403[M + H]+ 1a-79

CH₂OH 2HCl Colorless powderMS · APCI (m/z): 383[M + H]+ 1a-80

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 403[M + H]+ 1a-81

CH₂OH 2HCl Colorless powderMS · APCI (m/z): 383[M + H]+ 1a-82

CH₂OH 2HCl Colorless powderMS · APCI (m/z): 383[M + H]+ 1a-83

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 383[M + H]+ 1a-84

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 403[M + H]+ 1a-85

CH₂OH 2HCl Pale yellowish powderMS · APCI (m/z): 403[M + H]+ 1a-86

H 2HCl Purified powderMS · APCI (m/z): 343[M + H]+ 1a-87

H 2HCl Purified powderMS · APCI (m/z): 421[M + H]+ 1a-88

H 2HCl Purified powderMS · APCI (m/z): 343[M + H]+ 1a-89

H 2HCl Purified powderMS · APCI (m/z): 367[M + H]+

TABLE 1b

Example No. R²—X— R¹ Salt Physical properties, etc. 1b-1

H HCl Colorless powderMS · APCI (m/z): 374 [M + H]+ 1b-2

H HCl Colorless crystalGradually decomposedaround at melting point:233°C.MS · APCI (m/z): 354 [M + H]+ 1b-3

H HCl Colorless powderMS · APCI (m/z): 397 [M + H]+ 1b-4

H HCl Pale yellowish powderMS · APCI (m/z): 374 [M + H]+ 1b-5

H 2HCl Colorless powderMS · APCI (m/z): 344 [M + H]+ 1b-6

H HCl Colorless powderMS · APCI (m/z): 410 [M + H]+ 1b-7

H HCl Freeform Colorless powderMS · APCI (m/z): 364 [M + H]+ColorlesscrystalMelting point:129–130° C. (decomposed) 1b-8

H HCl Pale yellowish powderMS · APCI (m/z): 376 [M + H]+ 1b-9

H HCl ColorlessMS · APCI (m/z): 360 [M + H]+ 1b-10

H HCl Colorless powderMS · APCI (m/z): 436 [M + H]+ 1b-11

H HCl Colorless powderMS · APCI (m/z):396 [M + H]+ 1b-12

H HCl Colorless powderMS · APCI (m/z): 330[M + H]+ 1b-13

H HCl Pale yellowish powderMS · APCI (m/z):373 [M + H]+ 1b-14

H HCl Purified powderMS · APCI (m/z):330 [M + H]+ 1b-15

H HCl Purified powderMS · APCI (m/z):354 [M + H]+ 1b-16

H 2HCl Purified powderMS · APCI (m/z): 365, 363 1b-17

H 2HCl Purified powderMS · APCI (m/z): 365, 363 1b-18

H 2HCl Purified powderMS · APCI (m/z): 359 1b-19

H 2HCl Purified powderMS · APCI (m/z): 329 1b-20

H 2HCl Purified powderMS · APCI (m/z): 365, 363 1b-21

H 2HCl Purified powderMS · APCI (m/z): 359 1b-22

H HCl Colorless powderMS · APCI (m/z):330 [M + H]+ 1b-23

H HCl Purified powderMS · APCI (m/z):366, 364 1b-24

H HCl Purified powderMS · APCI (m/z): 355 1b-25

H HCl Colorless powderMS · APCI (m/z):376 [M + H]+ 1b-26

H HCl Purified powderMS · APCI (m/z): 398 1b-27

H HCl Purified powderMS · APCI (m/z): 358 1b-28

H HCl Purified powderMS · APCI (m/z): 366,364 1b-29

H HCl Purified powderMS · APCI (m/z): 366,364 1b-30

H HCl Purified powderMS · APCI (m/z): 330 1b-31

H 2HCl Purified powderMS · APCI (m/z): 456 1b-32

H HCl Purified powderMS · APCI (m/z): 373 1b-33

H HCl Colorless powderMS · APCI (m/z): 353 [M + H] 1b-34

H HCl Colorless powderMS · APCI (m/z):371 [M + H]+ 1b-35

H HCl Colorless powderMS · APCI (m/z):371 [M + H]+ 1b-36

H HCl Colorless powderMS · APCI (m/z):421 [M + H]+ 1b-37

H HCl Colorless powderMS · APCI (m/z):371 [M + H]+ 1b-38

H HCl Colorless powderMS · APCI (m/z):371 [M + H]+ 1b-39

H HCl Colorless powderMS · APCI (m/z): 367 [M + H] 1b-40

H HCl Pale brownish powderMS · APCI (m/z): 371 [M + H] 1b-41

H HCl Colorless powderMS · APCI (m/z):433, 431 [M + H] 1b-42

H HCl Colorless powderMS · APCI (m/z): 383 [M + H] 1b-43

H HCl Colorless powderMS · APCI (m/z): 387 [M + H] 1b-44

H HCl Colorless powderMS · APCI (m/z): 433,431 [M + H] 1b-45

H HCl Purified powderMS · APCI (m/z): 492, 490 1b-46

H HCl Purified powderMS · APCI (m/z): 406 1b-47

H HCl Purified powderMS · APCI (m/z): 379 1b-48

H HCl Colorless powderMS · APCI (m/z):385 [M + H]+ 1b-49

H HCl Purified powderMS · APCI (m/z): 448 1b-50

H 2HCl Purified powderMS · APCI (m/z): 445 1b-51

H 2HCl Purified powderMS · APCI (m/z): 431 1b-52

H 2HCl Purified powderMS · APCI (m/z): 487 1b-53

H 2HCl Purified powderMS · APCI (m/z): 471 1b-54

H 2HCl Purified powderMS · APCI (m/z): 417 1b-55

H 2HCl Purified powderMS · APCI (m/z): 444 1b-56

H 2HCl Purified powderMS · APCI (m/z): 486 1b-57

H 2HCl Purified powderMS · APCI (m/z): 470 1b-58

H HCl Colorless powderMS · APCI (m/z): 374[M + H]+ 1b-59

H HCl Colorless powderMS · APCI (m/z): 354[M + H]+ 1b-60

H HCl Colorless powderMS · APCI (m/z): 397[M + H]+ 1b-61

H HCl Colorless powderMS · APCI (m/z): 354[M + H]+ 1b-62

H HCl Colorless powderMS · APCI (m/z): 408[M + H]+ 1b-63

H HCl Yellowish powderMS · APCI (m/z): 376[M + H]+ 1b-64

H HCl Colorless powderMS · APCI (m/z): 330[M + H]+ 1b-65

Me HCl Purified powderMS · APCI (m/z): 388 [M + H]+ 1b-66

Me HCl Purified powderMS · APCI (m/z): 368 [M + H]+ 1b-67

Me HCl Purified powderMS · APCI (m/z): 388 [M + H]+ 1b-68

Me HCl Purified powderMS · APCI (m/z): 368 [M + H]+ 1b-69

Me HCl Purified powderMS · APCI (m/z): 388 [M + H]+ 1b-70

Me HCl Purified powderMS · APCI (m/z): 424 [M + H]+ 1b-71

Me HCl Purified powderMS · APCI (m/z): 386 [M + H]+

TABLE 1c

Exam- ple Physical properties, No. R²—X— R¹ Salt etc. 1c-1

H 2HCl Colorless powderMS · APCI (m/z):356 [M + H]+ 1c-2

H HCl Colorless powderMS · APCI (m/z):361 [M + H] 1c-3

H HCl Purified powderMS · APCI (m/z):362 1c-4

H HCl Colorless powderMS · APCI (m/z):355 [M + H]+ 1c-5

H HCl Colorless powderMS · APCI (m/z):375 [M + H] 1c-6

H HCl Colorless powderMS · APCI (m/z):383 [M + H]+ 1c-7

H 2HCl Purified powderMS · APCI (m/z): 404 1c-8

H 2HCl Colorless powderMS · APCI (m/z): 398[M + H] 1c-9

H HCl Purified powderMS · APCI (m/z): 427 1c-10

H HCl Colorless crystalMelting point: 211° C.(decomposed)MS · APCI(m/z): 307[M + H] 1c-11

H HCl Purified powderMS · APCI (m/z): 349 1c-12

H HCl Colorless powderMS · APCI (m/z): 377[M + H]+ 1c-13

H HCl Purified powderMS · APCI (m/z): 349 1c-14

H HCl Colorless powderMS · APCI (m/z):363 [M + H]+ 1c-15

H HCl Purified powderMS · APCI (m/z): 365 1c-16

H HCl Colorless powderMS · APCI (m/z): 389[M + H]+ 1c-17

H HCl Pale brownish purifiedresin stateMS · APCI (m/z):279 [M + H]+1c-18

H HCl Purified powderMS · APCI (m/z):293 [M + H]+ 1c-19

H HCl Purified powderMS · APCI (m/z):307 [M + H]+ 1c-20

H HCl Purified powderMS · APCI (m/z):335 [M + H]+ 1c-21

H HCl Purified powderMS · APCI (m/z):321 [M + H]+ 1c-22

H HCl Purified powderMS · APCI (m/z):335 [M + H]+ 1c-23

H HCl Colorless powderMS · APCI (m/z):357 [M + H]+ 1c-24

H HCl Colorless powderMS · APCI (m/z):357 [M + H]+ 1c-25

H HCl Colorless powderMS · APCI (m/z):373 [M + H]+ 1c-26

H HCl Colorless powderMS · APCI (m/z):362 [M + H]+ 1c-27

H HCl Colorless powderMS · APCI (m/z):376 [M + H]+ 1c-28

H HCl Pale brownish powderMS · APCI (m/z):363 [M + H]+ 1c-29

H HCl Colorless purifiedpowderMS · APCI (m/z): 395[M + H]+ 1c-30

H HCl Purified powderMS · APCI (m/z):321 [M + H]+ 1c-31

H HCl Purified powderMS · APCI (m/z):335 [M + H]+ 1c-32

H HCl Brownish purifiedresin stateMS · APCI (m/z):365 [M + H]+ 1c-33

H HCl Pale brownishpurified powderMS · APCI (m/z):365 [M + H]+ 1c-34

H HCl Pale brownishpurified resin stateMS · APCI (m/z):379 [M + H]+1c-35

H HCl Purified powderMS · APCI (m/z): 351 1c-36

H HCl Purified powderMS · APCI (m/z): 351 1c-37

H HCl Colorless purifiedpowderMS · APCI (m/z):365 [M + H]+ 1c-38

H HCl Colorless purifiedpowderMS · APCI (m/z):407 [M + H]+ 1c-39

H HCl Colorless purifiedpowderMS · APCI (m/z):351 [M + H]+ 1c-40

H HCl Colorless purifiedpowderMS · APCI (m/z):379 [M + H]+ 1c-41

H HCl Colorless purifiedpowderMS · APCI (m/z):333 [M + H]+ 1c-42

H 2HCl Purified powderMS · APCI (m/z): 370[M + H]+ 1c-43

H 2HCl Purified powderMS · APCI (m/z): 400[M + H]+ 1c-44

H HCl Colorless purifiedpowderMS · APCI (m/z): 409[M + H]+ 1c-45

H HCl Colorless purifiedpowderMS · APCI (m/z): 423[M + H]+ 1c-46

H HCl Purified powderMS · APCI (m/z):307 [M + H]+ 1c-47

H HCl Colorless powderMS · APCI (m/z): 335[M + H]+ 1c-48

H HCl Purified powderMS · APCI (m/z): 479[M + H]+ 1c-49

H HCl Purified powderMS · APCI (m/z): 498[M + H]+ 1c-50

H HCl Purified powderMS · APCI (m/z): 492[M + H]+ 1c-51

H 2HCl Purified powderMS · APCI (m/z): 492[M + H]+ 1c-52

H 2HCl Colorless powderMS · APCI (m/z): 452[M + H]+

TABLE 1d

Example Physical properties, No. R²—X— R¹ Salt etc. 1d-1 

H HCl Colorless powderMS · APCI (m/z): 333 [M + H]+ 1d-2 

H HCl Purified powderMS · APCI (m/z): 363 1d-3 

H HCl Purified powderMS · APCI (m/z): 377 1d-4 

H HCl Colorless powderMS · APCI (m/z): 361 [M + H]+ 1d-5 

H HCl Colorless powderMS · APCI (m/z) : 347 [M + H]+ 1d-6 

H HCl Colorless powderMS · APCI (m/z): 361 [M + H]+ 1d-7 

H HCl Colorless powderMS · APCI (m/z): 375 [M + H]+ 1d-8 

H HCl Purified powderMS · APCI (m/z): 403 [M + H]+ 1d-9 

H HCl Purified powderMS · APCI (m/z): 405 [M + H]+ 1d-10

H Freeform Purified powderMS · APCI (m/z): 390 1d-11

H HCl Colorless powderMS · APCI (m/z): 390 [M + H]+ 1d-12

H 2HCl Colorless powderMS · APCI (m/z): 390 [M + H]+ 1d-13

H HCl Purified powderMS · APCI (m/z): 446 [M + H]+ 1d-14

H 2HCl Colorless powderMS · APCI (m/z): 348 [M + H]+ 1d-15

H 2HCl Purified powderMS · APCI (m/z): 376 1d-16

H 2HCl Colorless powderMS · APCI (m/z): 390 [M + H]+ 1d-17

H 2HCl Colorless powderMS · APCI (m/z): 404 [M + H]+ 1d-18

H 2HCl Colorless powderMS · APCI (m/z): 392 [M + H]+ 1d-19

H HCl Colorless powderMS · APCI (m/z): 390 [M + H] 1d-20

H HCl Purified powderMS · APCI (m/z): 404 1d-21

H HCl Purified powderMS · APCI (m/z): 418 1d-22

H HCl Colorless powder 1d-23

H HCl Purified powderMS · APCI (m/z): 432 1d-24

H HCl Purified powderMS · APCI (m/z): 432 1d-25

H HCl Colorless crystalGradually decomposed ataround Melting point:198°C.MS · APCI (m/z):420 [M + H]+ 1d-26

H HCl Purified powderMS · APCI (m/z): 426 [M + H]+ 1d-27

H HCl Colorless crystalMelting point: 207–211° C.MS · APCI (m/z): 377[M + H] 1d-28

H HCl  Methanesulfonicacid Colorless crystalMelting point: 219° C.(decomposed)MS · APCI (m/z): 349 [M + H]+Colorless crystalMelting point:217–218° C.(decomposed) 1d-29

H HCl Colorless powderMS · APCI (m/z): 365 [M + H]+ 1d-30

H HCl Colorless powderMS · APCI (m/z): 397 [M + H]+ 1d-31

H HCl Pale brownish powderMS · APCI (m/z): 426 [M + H]+ 1d-32

H HCl Colorless crystalMelting point: 198–200° C.(decomposed)MS · APCI(m/z): 381 [M + H] 1d-33

H HCl Pale yellowish powderMS · APCI (m/z): 381 [M + H]+ 1d-34

H 2HCl Colorless crystalMelting point: >300° C.MS · APCI (m/z): 382 [M +H]+ 1d-35

H HCl Purified powderMS · APCI (m/z): 395 1d-36

H HCl Purified powderMS · APCI (m/z): 401 1d-37

H HCl Purified powderMS · APCI (m/z): 423 1d-38

H HCl Colorless powderMS · APCI (m/z): 429 [M + H]+ 1d-39

H HCl Colorless powderMS · APCI (m/z): 451 [M + H]+ 1d-40

H HCl Purified powderMS · APCI (m/z): 424 1d-41

H 2HCl Colorless powderMS · APCI (m/z): 438 [M + H] 1d-42

H 2HCl Colorless powderMS · APCI (m/z): 458 [M + H] 1d-43

H 2HCl Purified powderMS · APCI (m/z): 454 1d-44

H 2HCl Purified powderMS · APCI (m/z): 425 1d-45

H 2HCl Colorless powderMS · APCI (m/z): 426 [M + H]+ 1d-46

H HCl Colorless powderMS · APCI (m/z): 492 [M + H]+ 1d-47

H 2HCl Purified powderMS · APCI (m/z): 444 [M + H]+ 1d-48

H 2HCl Purified powderMS · APCI (m/z): 438 1d-49

H 2HCl Colorless powderMS · APCI (m/z): 466 [M + H] 1d-50

H 2HCl Purified powderMS · APCI (m/z): 494 1d-51

H HCl Purified powderMS · APCI (m/z): 437 1d-52

H Maleicacid Purified powderMelting point: 180–183° C. 1d-53

H HCl Purified powderMS · APCI (m/z): 465 1d-54

H HCl Purified powderMS · APCI (m/z): 521, 519 1d-55

H HCl Purified powderMS · APCI (m/z): 484 1d-56

H HCl Purified powderMS · APCI (m/z): 451 1d-57

H HCl Purified powderMS · APCI (m/z): 460 [M + H]+ 1d-58

H HCl Purified powderMS · APCI (m/z): 416 1d-59

H HCl Purified powderMS · APCI (m/z): 458 1d-60

H HCl Colorless powderMS · APCI (m/z): 452 [M + H] 1d-61

H 2HCl Colorless powderMS · APCI (m/z): 453 [M + H] 1d-62

H HCl Colorless powderMS · APCI (m/z): 458 [M + H] 1d-63

H HCl Colorless powderMS · APCI (m/z): 455 [M + H] 1d-64

H HCl Colorless powderMS · APCI (m/z): 461 [M + H]+ 1d-65

H HCl Purified powderMS · APCI (m/z): [M + H]+ 1d-66

H HCl Colorless powderMS · APCI (m/z): 467 [M + H]+ 1d-67

H HCl Purified powderMS · APCI (m/z): 500 [M + H]+ 1d-68

H HCl Colorless powderMS · APCI (m/z): 481 [M + H]+ 1d-69

H HCl Purified powderMS · APCI (m/z): 494 [M + H]+ 1d-70

H HCl Colorless powderMS · APCI (m/z): 482 [M + H]+ 1d-71

H HCl Purified powderMS · APCI (m/z): 466 [M + H]+ 1d-72

H 2HCl Purified powderMS · APCI (m/z): 467 [M + H]+ 1d-73

H HCl Purified powderMS · APCI (m/z): 472 [M + H]+ 1d-74

H 2HCl Purified powderMS · APCI (m/z): 514 [M + H]+ 1d-75

H HCl Purified powderMS · APCI (m/z): 377 1d-76

H HCl Purified powderMS · APCI (m/z): 377 1d-77

H 2HCl Colorless powderMS · APCI (m/z): 484 [M + H] 1d-78

H HCl Purified powderMS · APCI (m/z): 376 1d-79

H HCl Pale yellowish powderMS · APCI (m/z): 420 [M + H]+ 1d-80

H HCl Colorless powderMS · APCI (m/z): 419 [M + H] 1d-81

H HCl Colorless purified powderMS · APCI (m/z): 524 [M + H]+ 1d-82

H HCl Colorless purified powderMS · APCI (m/z): 453 [M + H]+ 1d-83

H HCl Colorless powderMS · APCI (m/z): 411 [M + H]+ 1d-84

H 2HCl Colorless purified powderMS · APCI (m/z): 481 [M + H]+ 1d-85

H HCl Colorless purified powderMS · APCI (m/z): 474 [M + H]+ 1d-86

H HCl Purified powderMS · APCI (m/z): 411 [M + H]+ 1d-87

H HCl Colorless purified powderMS · APCI (m/z): 411 [M + H]+ 1d-88

H HCl Colorless purified powderMS · APCI (m/z): 425 [M + H]+ 1d-89

H HCl Colorless powderMS · APCI (m/z): 397 [M + H]+ 1d-90

H Freeform Colorless solidMS · APCI (m/z): 460 [M + H]+ 1d-91

H HCl Colorless powderMS · APCI (m/z): 425 [M + H]+ 1d-92

H HCl Colorless powderMS · APCI (m/z): 397 [M + H] 1d-93

H HCl Purified powderMS · APCI (m/z): 410 1d-94

H HCl Purified powderMS · APCI (m/z): 340 [M + H] 1d-95

H HCl Purified powderMS · APCI (m/z): 365 [M + H] 1d-96

H HCl Colorless powderMS · APCI (m/z): 374 [M + H] 1d-97

H HCl Yellowish powderMS · APCI (m/z): 385 [M + H] 1d-98

H HCl Colorless powderMS · APCI (m/z): 382 [M + H] 1d-99

H HCl Purified powderMS · APCI (m/z): 330 [M + H]  1d-100

H HCl Purified powderMS · APCI (m/z): 346 [M + H]  1d-101

H HCl Colorless powderMS · APCI (m/z): 396 [M + H]  1d-102

H 2HCl Colorless powderMS · APCI (m/z): 341 [M + H]  1d-103

Me HCl Purified powderMS · APCI (m/z): 363 [M + H]  1d-104

H HCl Colorless powderMS · APCI (m/z): 406 [M + H]  1d-105

H HCl Colorless powderMS · APCI (m/z): 448 [M + H]  1d-106

H HCl Colorless powderMS · APCI (m/z): 434 [M + H]  1d-107

H HCl Colorless powderMS · APCI (m/z): 468 [M + H]  1d-108

H HCl Pale yellowish powderMS · APCI (m/z): 472 [M + H]  1d-109

H HCl Pale yellowish powderMS · APCI (m/z): 471 [M + H]  1d-110

H HCl Purified powderMS · APCI (m/z): 439 [M + H]+  1d-111

H HCl Colorless purified powderMS · APCI (m/z): 425 [M + H]+  1d-112

H HCl Purified powderMS · APCI (m/z): 453 [M + H]+  1d-113

H HCl Colorless purified powderMS · APCI (m/z): 454 [M + H]+  1d-114

H HCl Colorless purified powderMS · APCI (m/z): 438 [M + H]+  1d-115

H 2HCl Purified powderMS · APCI (m/z): 480 [M + H]+  1d-116

H HCl Colorless purified powderMS · APCI (m/z): 452 [M + H]+  1d-117

H HCl Colorless purified powderMS · APCI (m/z): 424 [M + H]+  1d-118

H HCl Colorless purified powderMS · APCI (m/z): 468 [M + H]+  1d-119

H HCl Colorless purified powderMS · APCI (m/z): 478 [M + H]+  1d-120

H HCl Colorless purified powderMS · APCI (m/z): 494 [M + H]+  1d-121

H 2HCl Colorless purified powderMS · APCI (m/z): 410  1d-122

H HCl Colorless purified powderMS · APCI (m/z): 478 [M + H]+  1d-123

H HCl Colorless purified powderMS · APCI (m/z): 452 [M + H]+  1d-124

H HCl Colorless purified powderMS · APCI (m/z): 488 [M + H]+  1d-125

H HCl Colorless purified powderMS · APCI (m/z): 406 [M + H]+  1d-126

H HCl Colorless powderMS · APCI (m/z): 438 [M + H]  1d-127

H HCl Colorless powderMS · APCI (m/z): 467 [M + H]  1d-128

H HCl Colorless powderMS · APCI (m/z): 454 [M + H]  1d-129

H HCl Colorless powderMS · APCI (m/z): 474 [M + H]  1d-130

H 2HCl Colorless powderMS · APCI (m/z): 481 [M + H]  1d-131

H 2HCl Colorless powderMS · APCI (m/z): 424 [M + H]  1d-132

H HCl Colorless powderMS · APCI (m/z): 438 [M + H]  1d-133

H HCl Yellow brownish powderMS · APCI (m/z): 467 [M + H]  1d-134

H HCl Colorless powderMS · APCI (m/z): 454 [M + H]  1d-135

H HCl Colorless powderMS · APCI (m/z): 474 [M + H]  1d-136

H 2HCl Pale brownish powderMS · APCI (m/z): 481 [M + H]  1d-137

H 2HCl Colorless powderMS · APCI (m/z): 424 [M + H]  1d-138

H 2HCl Pale yellowish powderMS · APCI (m/z): 468 [M + H]+  1d-139

H HCl Colorless powderMS · APCI (m/z): 411 [M + H]+  1d-140

H HCl Colorless powderMS · APCI (m/z): 468 [M + H]+  1d-141

H HCl Colorless powderMS · APCI (m/z): 469 [M + H]  1d-142

H HCl Colorless powderMS · APCI (m/z): 468 [M + H]+  1d-143

H HCl Colorless powderMS · APCI (m/z): 469 [M + H]+  1d-144

H HCl Purified powderMS · APCI (m/z): 363 [M + H]+  1d-145

H HCl Colorless powderMS · APCI (m/z): 349 [M + H]+  1d-146

H HCl Purified powderMS · APCI (m/z): 381 [M + H]+  1d-147

H HCl Colorless powderMS · APCI (m/z): 425 [M + H]+  1d-148

H 2HCl Colorless powderMS · APCI (m/z): 425 [M + H]+  1d-149

H 2HCl Colorless resin stateMS · APCI (m/z): 430 [M + H]+  1d-150

H HCl Colorless powderMS · APCI (m/z): 439 [M + H]+  1d-151

H 2HCl Purified powderMS · APCI (m/z): 438 [M + H]+  1d-152

H 2HCl Colorless powderMS · APCI (m/z): 438 [M + H]+

TABLE 2

Exam- ple Physical No. R²—X— R¹ Salt properties, etc. 2-1

Me 2HCl Purified powderMS · APCI (m/z):366 2-2

Me 2HCl Purified powderMS · APCI (m/z):366 2-3

Me 2HCl Purified powderMS · APCI (m/z):366 2-4

Me 2HCl Purified powderMS · APCI (m/z):366 2-5

Me 2HCl Purified powderMS · APCI (m/z):366 2-6

Me 2HCl Purified powderMS · APCI (m/z):371 2-7

Me 2HCl Purified powderMS · APCI (m/z):359 2-8

Me 2HCl Purified powderMS · APCI (m/z):347

TABLE 3

Example Physical properties, No. R²—X— R¹ Salt etc. 3-1

H 2HCl Colorless powderMS · APCI (m/z): 370[M + H]+ 3-2

H 2HCl Colorless powderMS · APCI (m/z): 370[M + H]+ 3-3

H 2HCl Colorless powderMS · APCI (m/z): 357[M + H]+ 3-4

H 2HCl Resin stateMS · APCI (m/z): 371[M + H]+ 3-5

H 2HCl Resin stateMS · APCI (m/z): 371[M + H]+ 3-6

H 2HCl Resin stateMS · APCI (m/z): 400[M + H]+ 3-7

H 2HCl Resin stateMS · APCI (m/z): 384[M + H]+ 3-8

H HCl Colorless powderMS · APCI (m/z): 337[M + H]+ 3-9

H HCl Colorless powderMS · APCI (m/z): 335[M + H]+  3-10

H HCl Pale yellowish powderMS · APCI (m/z): 363[M + H]+  3-11

H 2HCl Colorless powderMS · APCI (m/z): 362[M + H]+  3-12

H HCl Colorless powderMS · APCI (m/z): 455[M + H]+

TABLE 4

Example Physical properties, No. R²—X— R¹ Salt etc. 4-1 

H 2HCl Pale yellowish powderMS · APCI (m/z): 391 [M + H]+ 4-2 

H 2HCl Colorless powderMS · APCI (m/z): 346 [M + H]+ 4-3 

H 2HCl Pale yellowish powderMS · APCI (m/z): 371 [M + H]+ 4-4 

H 2HCl Colorless powderMS · APCI (m/z): 414 [M + H]+ 4-5 

H HCl Colorless powderMelting point: >300° C.MS · APCI (m/z): 347 [M +H]+ 4-6 

H 2HCl Colorless powderMS · APCI (m/z): 425 427[M + H]+ 4-7 

H 2HCl Colorless powderMS · APCI (m/z): 393 [M + H]+ 4-8 

H 2HCl Colorless powderMS · APCI (m/z): 381 4-9 

H 2HCl Colorless powderMS · APCI (m/z): 352 [M + H]+ 4-10

H 2HCl Pale yellowish powderMS · APCI (m/z): 391 [M + H]+ 4-11

H HCl Colorless powderMS · APCI (m/z): 392 [M + H]+ 4-12

H HCl Colorless powderMS · APCI (m/z): 372 [M + H]+ 4-13

H HCl Colorless powderMS · APCI (m/z): 426 [M + H]+ 4-14

H HCl Colorless powderMS · APCI (m/z): 382 [M + H]+ 4-15

H HCl Colorless powderMS · APCI (m/z): 394 [M + H]+ 4-16

H HCl Colorless powderMelting point: 80° C.-(Decomposed)MS · APCI (m/z):348 [M + H]+ 4-17

H HCl Colorless powderMS · APCI (m/z): 414 [M + H]+ 4-18

H HCl Pale yellowish powderMS · APCI (m/z): 391 [M + H]+ 4-19

H 2HCl Colorless powderMS · APCI (m/z): 374 [M + H]+ 4-20

H HCl Colorless purified powderMS · APCI (m/z): 297 [M + H]+ 4-21

H HCl Purified powderMS · APCI (m/z): 325 [M + H]+ 4-22

H HCl Colorless purified powderMS · APCI (m/z): 397 [M + H]+ 4-23

H HCl Colorless powderMS · APCI (m/z): 438 [M + H]+ 4-24

H HCl Colorless powderMS · APCI (m/z): 423 [M + H]+ 4-25

H HCl Colorless.purified powderMS · APCI (m/z): 471 [M + H]+ 4-26

H HCl Colorless powderMS · APCI (m/z): 367 [M + H]+ 4-27

H HCl Colorless powderMS · APCI (m/z): 351 [M + H]+ 4-28

H HCl Colorless powderMS · APCI (m/z): 399 [M + H]+ 4-29

H 2HCl Colorless powderMS · APCI (m/z): 414 [M + H]+ 4-30

H HCl Colorless powderMS · APCI (m/z): 429 [M + H]+ 4-31

H HCl Colorless powderMS · APCI (m/z): 444 [M + H]+ 4-32

H HCl Colorless powderMS · APCI (m/z): 486 [M + H]+

TABLE 5

Reference Physical Example No. R²—X— R¹ Salt properties, etc. 3-1 

H Freeform Yellowish crystalMelting point: 156–158° C. 3-2 

H Freeform Pale brownish crystalMelting point: 110–122° C. 3-3 

H Freeform Colorless crystalMelting point: 152–154° C. 3-4 

H Freeform Pale brownish crystalMelting point: 77–80° C. 3-5 

H Freeform Pale yellowishneedle-like crystalMelting point: 107–108° C.3-6 

H Freeform Yellowishneedle-like crystalMelting point: 84° C.- 3-7 

H Freeform Colorless crystalMelting point: 128–129° C. 3-8 

H Freeform Colorless crystalMelting point: 140–141° C. 3-9 

H Freeform Pale yellowish crystalMelting point: 116–118° C. 3-10

H 2HCl Colorless crystalMelting point: >300° C. 3-11

H Freeform Pale yellowishneedle-like crystalMelting point: 92–94° C.3-12

H Freeform Brownish crystalMelting point: 120–123° C. 3-13

H Freeform PowderMS · APCI (m/z): 228, 226 3-14

H Freeform OilMS · APCI (m/z): 228, 226 3-15

H Freeform OilMS · APCI (m/z): 228, 226 3-16

H Freeform Oil 3-17

H Freeform PowderMS · APCI (m/z): 261 3-18

H Freeform OilMS · APCI (m/z): 221 3-19

H Freeform PowderMS · APCI (m/z): 218 3-20

H Freeform PowderMS · APCI (m/z): 218 3-21

H Freeform Yellowish oilMS · APCI (m/z):239 [M + H]+ 3-22

H Freeform Yellowish foamMS · APCI (m/z):311 [M + H]+ 3-23

H Freeform Yellowish oilMS · APCI (m/z):312 [M + H]+ 3-24

H Freeform Colorless oil 3-25

H Freeform Colorless oil 3-26

H Freeform PowderMS · APCI (m/z): 269 3-27

H Freeform Yellowish oilMS · APCI (m/z):259 [M + H]+ 3-28

H Freeform OilMS · APCI (m/z): 250 3-29

H Freeform PowderMS · APCI (m/z): 236 3-30

H Freeform PowderMS · APCI (m/z): 234 3-31

H Freeform OilMS · APCI (m/z): 234 3-32

H Freeform PowderMS · APCI (m/z): 284 3-33

H Freeform PowderMS · APCI (m/z): 231 3-34

H Freeform PowderMS · APCI (m/z): 234 3-35

H Freeform Pale brownish crystalMelting point: 99–102° C.MS · APCI(m/z):216 [M + H] 3-36

H Freeform Yellowish resinMS · APCI (m/z):234 [M + H] 3-37

H Freeform Pale reddish brownish powderMS · APCI (m/z): 296,294 [M + H]3-38

H Freeform Pale reddish brownish powderMS · APCI (m/z):246 [M + H]Reference Physical Example No. R¹—X—Y— R² Salt properties, etc. 3-39

H Freeform Oil 3-40

H Freeform Oil 3-41

H Freeform Yellowish crystalMelting point: 135–136.5° C. 3-42

H Freeform Yellowish powderMS · APCI (m/z):242 [M + H]+ 3-43

H Freeform Yellowish crystalMelting point: 81.5–83.5° C. 3-44

H Freeform Reddish liquidMS · APCI (m/z):266 [M + H]+ 3-45

H Freeform Dark reddish powderMS · APCI (m/z):253 [M + H]+ 3-46

H Freeform PowderMS · APCI (m/z): 229, 227 3-47

H Freeform Oil 3-48

H Freeform PowderMS · APCI (m/z): 193 3-49

H Freeform Oil 3-50

H Freeform Colorless oil Reference Physical Example No. R²—X— R¹ Saltproperties, etc. 3-51

H Freeform Colorless oil 3-52

H Freeform Colorless oil 3-53

H Freeform Yellowish oil 3-54

H Freeform Colorless oil 3-55

H Freeform Colorless oil 3-56

H Freeform Yellowish oil 3-57

H Freeform Colorless foam 3-58

H Freeform Colorless oil 3-59

H Freeform Colorless oil 4

H Freeform Pale yellowish solidMelting point: 153–155° C. 5-1 

H 2HCl Yellowish crystalMelting point: 219–222° C. 5-2 

H 2HCl Colorless powderMS · APCI (m/z):217 [M + H]+ 5-3 

H 2HCl Colorless crystalMelting point: 215–218° C. 5-4 

H 2HCl Colorless crystalMelting point: 245–250° C. 5-5 

H 2HCl Colorless crystalMelting point: 303° C. 5-6 

H 2HCl Yellowish crystalMelting point: 234–237° C. 7-1 

Me Freeform Colorless crystalMelting point: 121–123° C. 7-2 

Me Freeform Yellowish crystalMelting point: 164–166° C. 7-3 

Me Freeform Yellowish crystalMelting point: 40–43° C. 7-4 

Me Freeform Pale yellowish crystalMelting point: 147–148° C. 7-5 

Me Freeform Colorless crystalMelting point: 111–112° C. 7-6 

Me Freeform Pale brownish crystalMelting point: 121–124° C. 7-7 

Me Freeform Yellowish crystalMelting point: 58–59° C. 7-8 

Me Freeform Colorless crystalMelting point: 182–184° C. 7-9 

Me Freeform Pale brownish crystalMelting point: 76–79° C. 7-10

CH₂OH 2HCl Pale yellowish solidMS · APCI (m/z):267 [M + H]+ 7-11

CH₂OH 2HCl Colorless solidMS · APCI (m/z):247 [M + H]+ 7-12

CH₂OH 2HCl Yellowish powderMS · APCI (m/z):267 [M + H]+ 7-13

CH₂OH Freeform Colorless oilMS · APCI (m/z):247 [M + H]+ 7-14

CH₂OH 2HCl Pale yellowish solidMS · APCI (m/z):269 [M + H]+ 7-15

CH₂OH 2HCl Colorless powderMS · APCI (m/z):247 [M + H]+ 7-16

CH₂OH 2HCl Colorless solidMS · APCI (m/z):247 [M + H]+ 7-17

CH₂OH 2HCl Yellowish powderMS · APCI (m/z):267 [M + H]+ 7-18

CH₂OH 2HCl Pale yellowish solidMS · APCI (m/z):267 [M + H]+ 7-19

Me 2HCl Colorless resin stateMS · APCI (m/z):207 [M + H]+ 7-20

Me Freeform PowderMS · APCI (m/z): 311 7-21

Me 7-22

Me 7-23

Me 8-1 

H Freeform Colorless resinMS · APCI (m/z):207 [M + H]+ 8-2 

H Freeform Colorless crystalMelting point: 109–112° C. 8-3 

H Freeform Pale brownish resinMS · APCI (m/z):207 [M + H]+ 8-4 

H Freeform Colorless crystalMelting point: 85–87° C.

TABLE 6

Reference Example Physical properties, No. R²—X— R¹ Salt etc. 9-1

H HCl Colorless crystalMelting point:271° C. 9-2

H HCl Colorless crystalMelting point: 289° C. 9-3

H HCl Colorless crystalMelting point:253–254° C. 9-4

H HCl Pale yellowishcrystalMelting point: 230° C. 9-5

H Free form Colorless crystalMelting point:70–72° C. 9-6

H Free form Colorless crystalMelting point:58–59° C. 9-7

H HCl Colorless crystalMelting point: 284° C.(decomposed) 9-8

H HCl Colorless crystalMelting point:279–280° C.(decomposed) 9-9

H HCl Colorless crystalMelting point: 275° C.(decomposed) 9-10

H HCl Colorless crystalMelting point:275–276° C.(decomposed) 9-11

H HCl Colorless crystalMelting point: 194° C. 9-12

H Free form Pale yellowishcrystalMelting point:222–223° C. 9-13

H Free form CrystalMelting point: 91–94° C.MS # APCI (m/z): 229, 2279-14

H Free form PowderMS # APCI (m/z): 229, 227 9-15

H Free form PowderMS # APCI (m/z): 223 9-16

H Free form PowderMS # APCI (m/z): 193 9-17

H Free form PowderMS # APCI (m/z): 229, 227 9-18

H H 9-19

H Free form Oil 9-20

H 9-21

H 9-22

H Free form Colorless powderMS # APCI (m/z): 240(M + H+)+ 9-23

H 9-24

H Free form PowderMS # APCI (m/z): 222 9-25

H Free form Oil 9-26

H Free form PowderMS # APCI (m/z): 262, 260 9-27

H Free form PowderMS # APCI (m/z): 194 9-28

H Free form OilMS # APCI (m/z): 320 9-29

H Free form PowderMS # APCI (m/z): 356, 354 9-30

H Free form PowderMS # APCI (m/z): 270 9-31

H Free form PowderMS # APCI (m/z): 243 9-32

H Free form Oil 9-33

H Free form PowderMS # APCI (m/z): 237 9-34

H HCl Colorless crystalMelting point:215–218° C.MS # APCI (m/z): 217[M + H] 9-35

H Free form Yellowish oil 9-36

H Free form Yellowish oil 9-37

H Free form Yellowish oil 9-38

H Free form Colorless oil 9-39

H Free form Colorless oil 9-40

H HCl Colorless crystalMelting point:253–254° C.MS # APCI (m/z): 231[M + H] 9-41

H HCl Pale greenmelting point: 270–285° C.MS # APCI (m/z): 235 [M + H]9-42

H HCl Colorless crystalmelting point: 283–284° C.MS # APCI (m/z):297,295 [M + H] 9-43

H HCl Colorless crystalmelting point: 246–247° C.MS # APCI (m/z): 247[M + H] 9-44

H HCl Colorless crystalmelting point: 285–294° C.MS # APCI (m/z): 251[M + H] 9-45

H HCl Colorless crystalmelting point: >300° C.MS # APCI (m/z): 297,295[M + H] 9-46

H Free form Pale brownish semi-solidMS # APCI (m/z): 194 [M +H]IR(cm⁻¹): 3351 9-47

H HCl Yellow brownish crystalmelting point:238–240° C. 9-48

H HCl Pale brownish crystalmelting point: 180° C.(decomposed) 9-49

H Free form 9-50

H Free form 9-51

H Free form 9-52

H Free form 9-53

H Free form 9-54

H Free form 9-55

H Free form 9-56

H Free form 9-57

H Free form 9-58

H HCl Pale brownish powderMS # APCI (m/z): 238[M + H]+ 9-59

H HCl Colorless powderMS # APCI (m/z): 218[M + H]+ 9-60

H HCl Colorless crystalmelting point: 234–235° C. (decomposed) 9-61

H HCl Colorless crystalmelting point: 126° C. 9-62

H HCl Pale yellowishcrystalmelting point: 206–207° C. (decomposed) 9-63

H HCl Pale yellowishcrystalmelting point: 148–150° C. (decomposed) 9-64

H HCl Colorless crystalmelting point: 189–191° C. (decomposed) 10-2

Me Free form Colorless liquidMS # APCI (m/z):252 [M + H]+ 10-3

Me Free form Colorless crystalMelting point:73–76° C. 10-4

Me Free form Colorless liquidMS.AFCI(m/z):252 [M + H]+ 10-5

Me Free form Colorless crystalMelting point:88–89° C. 10-6

Me Free form Colorless crystalMelting point:90–94° C. 10-7

Me Free form Colorless crystalMelting point:97–100° C. 10-8

Me Free form Colorless crystalMelting point:150–154° C.

TABLE 7

Reference Example Physical properties, No. R²—X— R¹ Salt etc. 11-1

H HCl Colorless solidMelting point:150–153° C.MS # APCI (m/z): 247[M +H]+ 11-2

H 2HCl Colorless crystalMelting point: 294–295° C. 11-3

H Free form Colorless crystalMelting point:185.5–186° C. 11-4

H HCl Colorless solidMelting point: >300° C.MS # APCI (m/z): 219[M + H]+11-5

H Free form Colorless solidMelting point:163–166° C. 11-6

H Free form Colorless liquidMS # APCI (m/z): 239[M + H] 11-7

H Free form Colorless liquidMS # APCI (m/z): 262[M + H] 11-8

H Free form Colorless liquid 11-9

H Free form Colorless liquid 11-10

H Free form LiquidMS # APCI (m/z): 171[M + H] 11-11

H Free form Pale yellowish oilMS # APCI (m/z): 213 11-12

H Free form Colorless oilMS # APCI (m/z): 241[M + H]+ 11-13

H Free form Pale yellowish oilMS # APCI (m/z): 213 11-14

H HCl Colorless liquidMS # APCI (m/z):227[M + H]+ 11-15

H Free form Pale yellowish oilMS # APCI (m/z): 229 11-16

H Free form Colorless oilMS # APCI (m/z): 253[M + H]+ 11-17

H HI Colorless powderMS # APCI (m/z):143[M + H]+ 11-18

H Free form Colorless crystalMS # APCI (m/z): 157 11-19

H Free form Colorless crystalMS # APCI (m/z): 171 11-20

H Free form Colorless crystalMS # APCI (m/z): 199 11-21

H Free form Colorless crystalMS # APCI (m/z): 185 11-22

H Free form Colorless crystalMelting point: 142° C.(Decomposed)MS # APCI(m/z):199[M + H]+ 11-23

H Free form Colorless oilMS # APCI (m/z): 185 11-24

H Free form Colorless oilMS # APCI (m/z): 199 11-25

H Free form Colorless resinMS # APCI (m/z): 229 [M + H]+ 11-26

H Free form Colorless resinMS # APCI (m/z): 229 [M + H]+ 11-27

H Free form Colorless resinMS # APCI (m/z): 243 [M + H]+ 11-28

H Free form Colorless oilMS # APCI (m/z): 215 11-29

H Free form Colorless oilMS # APCI (m/z): 215 11-30

H Free form Colorless resinMS # APCI (m/z): 229 [M + H]+ 11-31

H Free form Colorless resinMS # APCI (m/z): 271 [M + H]+ 11-32

H Free form Colorless resinMS # APCI (m/z): 243 [M + H]+ 11-33

H Free form Colorless resinMS # APCI (m/z): 197 [M + H]+ 11-34

H Free form Pale brownish resin 11-35

H Free form Pale brownish resin 11-36

H Free form Pale brownish resin 11-37

H Free form Pale brownish resin 11-38

H Free form Pale brownish resin

TABLE 8

Reference Example Physical properties, No. R²—X— R¹ Salt etc. 12-1

H Free form Colorless oilMS # APCI (m/z): 197[M + H]+ 12-2

H Free form Colorless liquid 12-3

H Free form Pale yellowish oilMS # APCI (m/z): 241 12-4

H Free form Colorless oilMS # APCI (m/z): 225[M + H]+ 12-5

H Free form Colorless oilMS # APCI (m/z): 211[M + H]+ 12-6

H Free form Colorless oilMS # APCI (m/z): 225[M + H]+ 12-7

H Free form Colorless oilMS # APCI (m/z): 239[M + H]+ 12-8

H Free form Colorless liquidMS # APCI (m/z):267 [M + H]+ 12-9

H Free form Colorless liquidMS # APCI (m/z):269 [M + H]+ 12-10

H Free form Colorless oilMS # APCI (m/z): 254 12-11

H HCl Colorless oilMS # APCI (m/z): 254[M + H]+ 12-12

H 2HCl Colorless powderMS # APCI (m/z):254 [M + H]+ 12-13

H HCl Colorless resinMS # APCI (m/z): 310[M + H]+ 12-14

H Free form Colorless solidMS # APCI (m/z): 240 12-15

H 2HCl Colorless powderMS # APCI (m/z):254 [M + H]+ 12-16

H 2HCl Colorless powderMS # APCI (m/z):268 [M + H]+ 12-17

H 2HCl Colorless powderMS # APCI (m/z):256 [M + H]+ 12-18

H Free form Colorless powderMS # APCI (m/z): 254[M + H] 12-19

H Free form Colorless solidMelting point:93–96° C. 12-20

H Free form Colorless solidMelting point:242–245° C. 12-21

H Free form Colorless liquidMS # APCI (m/z): 282[M + H] 12-22

H Free form Colorless solidMelting point:173–176° C. 12-23

H Free form Colorless solidMelting point:135–137° C. 12-24

H Free form Colorless crystalMelting point:90–92° C. 12-25

H Free form Colorless crystalMelting point:152–153° C. 12-26

H Free form Colorless liquidMS # APCI (m/z): 241[M + H] 12-27

H Free form Colorless crystalMelting point:75–80° C. 12-28

H Free form Colorless crystalMelting point:170–173° C. 12-29

H Free form Colorless oilMS # APCI (m/z): 290[M + H]+ 12-30

H HCl Pale brownish solidMelting point:230–233° C. 12-31

H 2HCl Pale yellowish solidMS # APCI (m/z):246 [M + H]+ 12-32

H Free form Colorless solidMelting point:150–155° C. 12-33

H Free form Colorless solidMelting point:65–69° C. 12-34

H Free form Colorless solidMelting point:166–170° C. 12-35

H Free form Colorless oilMS # APCI (m/z): 293[M + H]+ 12-36

H Free form Colorless powderMS # APCI (m/z): 315[M + H]+ 12-37

H Free form Colorless solidMelting point:185–189° C. 12-38

H Free form Colorless liquidMS # APCI (m/z): 302[M + H] 12-39

H Free form Colorless crystalMelting point:131–132° C. 12-40

H Free form Colorless solidMelting point:81–83° C. 12-41

H Free form Colorless solidMelting point:185–189° C. 12-42

H 2HCl Colorless powderMS # APCI (m/z):290 [M + H]+ 12-43

H HCl Colorless solidMS # APCI (m/z):356 [M + H]+ 12-44

H Free form Colorless crystalMelting point:59–60° C. 12-45

H Free form Colorless liquidMS # APCI (m/z): 302 12-46

H Free form Colorless liquidMS # APCI (m/z): 330[M + H] 12-47

H Free form Colorless powderMS # APCI (m/z): 301 12-48

H Free form Colorless liquidMS # APCI (m/z): 358 12-49

H Free form Colorless crystalMelting point:120–121° C. 12-50

H Free form Pale yellowishcrystalMelting point:119–120° C. 12-51

H Free form Colorless crystalMelting point:144–145° C. 12-52

H Free form Yellowish crystalMelting point:140–141° C. 12-53

H Free form Colorless crystalMelting point:110–111° C. 12-54

H HCl Colorless crystalMelting point: 97–° C.MS # APCI (m/z): 324[M +H]+ 12-55

H Free form Colorless solidMelting point:245–248° C. 12-56

H Free form Colorless solidMelting point:202–205° C. 12-57

H Free form Colorless crystalMelting point:150–153° C. 12-58

H Free form Colorless liquidMS # APCI (m/z): 317[M + H] 12-59

H Free form Colorless crystalMelting point:158–162° C. 12-60

H Free form Colorless liquidMS # APCI (m/z): 319[M + H] 12-61

H HCl Colorless powderMS # APCI (m/z): 325[M + H]+ 12-62

H Free form Colorless crystalMelting point:148–150° C. 12-63

H Free form Colorless powderMS # APCI (m/z): 331[M + H]+ 12-64

H Free form Colorless resinMS # APCI (m/z): 364[M + H]+ 12-65

H Free form Colorless oilMS # APCI (m/z): 345[M + H]+ 12-66

H Free form Colorless oilMS # APCI (m/z): 358[M + H]+ 12-67

H Free form Colorless crystalMelting point: 70° C. 12-68

H Free form Colorless crystalMelting point:188–190° C. 12-69

H 2HCl Colorless crystalMelting point: 180° C.(Decomposed)MS # APCI(m/z): 331[M + H]+ 12-70

H Free form SligHtly brownishcrystalMelting point:214–216° C. 12-71

H Free form Colorless liquidMS # APCI (m/z):378 [M + H]+ 12-72

H HCl Colorless powderMS # APCI (m/z): 229[M + H]+ 12-73

H Free form Colorless oilMS # APCI (m/z): 241 12-74

H Free form Colorless crystalMS # APCI (m/z): 241 12-75

H Free form 12-76

H Free form Colorless oilMS # APCI (m/z): 240 12-77

H Free form Colorless powderMS # APCI (m/z):284 [M + H]+ 12-78

H Free form Pale yellowish crystalMelting point: 99–104° C.MS # APCI(m/z):283[M + H]+ 12-79

H Free form Colorless resinMS # APCI (m/z):389 [M + H]+ 12-80

H Free form Colorless resinMS # APCI (m/z):317 [M + H]+ 12-81

H Free form Colorless powderMS # APCI (m/z):275 [M + H]+ 12-82

H Free form Colorless foam 12-83

H Free form Pale brownish resin 12-84

H Free form Pale brownish resin 12-85

H Free form Pale brownish resin 12-86

H Free form Colorless powderMS # APCI (m/z):275 [M + H]+ 12-87

H Free form Colorless powderMS # APCI (m/z):289 [M + H]+ 12-88

H HCl Colorless solidMS # APCI (m/z): 261[M + H]+ 12-89

H HCl Colorless solidMelting point:277–279° C.MS # APCI (m/z): 324[M +H]+ 12-90

H HCl Colorless solidMS # APCI (m/z): 289[M + H]+ 12-91

H Free form Colorless crystalMS # APCI (m/z): 274 12-92

H Free form Pale brownish resin 12-93

H Free form Pale brownish resin 12-94

H Free form Pale brownish resin 12-95

H Free form Pale brownish resin 12-96

H Free form Pale brownish resin 12-97

H Free form Colorless crystalMelting point:152–153° C. 13-1

H Free form Brownish oilMS # APCI (m/z): 221[M + H]+ 13-2

H Free form Pale yellowish powderMS # APCI (m/z): 221[M + H]+ 13-3

H Free form Pale yellowish oilMS # APCI (m/z): 237[M + H]+ 13-4

H Free form Brownish powderMS # APCI (m/z): 226[M + H]+ 13-5

H Free form Brownish oilMS # APCI (m/z): 240[M + H]+ 13-6

H Free form Brownish oilMS # APCI (m/z): 227[M + H]+ 13-7

H HBr Pale brownish powderMS # APCI (m/z): 261[M + H]+ 13-8

H HI Yellowish powderMS # APCI (m/z): 204[M + H] 13-9

H HI Yellowish powderMS # APCI (m/z): 229[M + H] 13-10

H HI Yellowish powderMS # APCI (m/z): 238[M + H] 13-11

H Free form Yellowish powderMS # APCI (m/z): 249[M + H] 13-12

H Free form Yellowish powderMS # APCI (m/z): 246[M + H] 13-13

H HI Yellowish powderMS # APCI (m/z): 194[M + H] 13-14

H HI Yellowish powderMS # APCI (m/z): 210[M + H] 13-15

H HI Yellowish powderMS # APCI (m/z): 260[M + H] 13-16

H 2HI Yellowish powderMS # APCI (m/z):205 [M + H] 13-17

Me HI Yellowish powderMS # APCI (m/z): 227[M + H] 13-18

H Free form Colorless semi-solidMS # APCI (m/z): 270[M + H] 13-19

H Free form Colorless semi-solidMS # APCI (m/z): 312[M + H] 13-20

H Free form Colorless resinMS # APCI (m/z): 298[M + H] 13-21

H Free form Colorless oilMS # APCI (m/z): 332[M + H] 13-22

H HCl Colorless powderMelting point:>300° C.MS # APCI (m/z): 336[M + H]13-23

H HI Brownish powder 13-24

H Free form Pale brownish resin 13-25

H Free form Pale brownish resin 13-26

H Free form Pale brownish resin 13-27

H Free form Pale brownish resin 13-28

H Free form Pale brownish resin 13-29

H Free form Pale brownish resin 13-30

H Free form Pale brownish resin 13-31

H Free form Colorless powderMS # APCI (m/z): 342[M + H]+ 13-32

H HI Colorless powderMS # APCI (m/z): 315[M + H]+ 13-33

H HI Colorless powderMS # APCI (m/z): 352[M + H]+ 13-34

H HI Pale brownish powder 13-35

H Free form Brownish oil 13-36

H Free form Brownish oil 13-37

H Free form Brownish oil 13-38

H Free form Brownish oil 13-39

H Free form Brownish oil 13-40

H Free form Brownish oil 13-41

H Free form 13-42

H HI Brownish powder 13-43

H Free form 13-44

H Free form 13-45

H HI Brownish powder 13-46

H Free form 13-47

H Free form Colorless crystalMelting point:199–202° C.MS # APCI (m/z):332[M + H]+ 13-48

H Free form Pale brownishpowderMS # APCI (m/z): 275[M + H]+ 13-49

H Free form Colorless powderMS # APCI (m/z): 332[M + H]+ 13-50

H Free form Colorless powderMS # APCI (m/z): 332[M + H]+ 13-51

H Free form Colorless powderMS # APCI (m/z): 332[M + H]+ 13-52

H Free form Colorless powderMS # APCI (m/z): 333[M + H]+ 14-1

H HCl Colorless resinMS # APCI (m/z): 227[M + H]+ 14-2

H HCl Colorless powderMS # APCI (m/z): 213[M + H]+ 14-3

H Free form Pale reddish crystalMelting point:144–145° C. 14-4

H Free form Colorless oilMS # APCI (m/z): 289[M + H]+ 14-5

H HCl Colorless powderMS # APCI (m/z): 199[M + H]+ 14-6

H Free form Pale yellowish oilMS # APCI (m/z): 171[M + H]+ 14-7

H Free form Colorless oilMS # APCI (m/z): 289[M + H]+ 14-8

H 2HCl Brownish powderMS # APCI (m/z): 294[M + H]+ 14-9

H Free form Colorless powderMS # APCI (m/z): 303[M + H]+ 14-10

H Free form Colorless oilMS # APCI (m/z): 302[M + H]+ 14-11

H Free form Colorless oilMS # APCI (m/z) 14-12

H Free form Colorless crystalMelting point:188–193° C. 14-13

H Free form Pale yellowishcrystalMelting point:194–196° C. 14-14

H Free form Slightly yellowishresinMS # APCI (m/z): 356[M + H]+ 14-15

H Free form Slightly yellowishresinMS # APCI (m/z): 356[M + H]+ 14-16

H Free form Brownish oilMS # APCI (m/z): 316[M + H]+

1. A method for treating a disease in a patient selected from amongdiabetes, hyperglycemia, hyperinsulinemia, diabetes complications,obesity, overeating, and disorders of lipid metabolism comprisingadministering to a patient in need thereof a pharmaceutical formulationcomprising a compound represented by the formula:

wherein A represents —CH₂— or —S—, R¹ represents a hydrogen atom, alower alkyl group, a hydroxy lower alkyl group or a lower alkoxy loweralkyl group, and R² represents: (1) a cyclic group which may besubstituted, where the cyclic group portion represents (i) a monocyclic,bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclicor tricyclic heterocyclic group; or (2) an amino group which may besubstituted; or a pharmaceutically acceptable salt thereof; and one ormore pharmaceutically acceptable excipients.
 2. The method according toclaim 1, wherein the disease is diabetes.
 3. The method according toclaim 1, wherein the disease is type-2 diabetes.
 4. The method accordingto any one of claims 1, 2, or 3, wherein R² is (1) a cyclic group whichmay have 1 to 3 substituents which are the same or different and areselected from the substituents of Group A listed below, where the cyclicgroup portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbongroup, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group,or (2) an amino group which may have 1 or 2 substituents which are thesame or different and selected from the substituents of Group B listedbelow; Substituents of Group A: a halogen atom; cyano group; nitrogroup; oxo group; hydroxy group; carboxy group; oxidyl group; aminogroup; carbamoyl group; aminosulfonyl group; lower alkyl group; loweralkoxy group; lower alkanoyl group; lower alkoxycarbonyl group; loweralkoxy-substituted lower alkanoyl group; loweralkoxycarbonyl-substituted lower alkoxy group; loweralkoxycarbonyl-substituted lower alkoxycarbonyl group; lower alkylthiogroup; lower alkylsulfonyl group; di-lower alkylamino-substituted loweralkoxy group; di-lower alkylaminocarbonyloxy group; lower alkyl groupsubstituted by one or more groups selected from an amino group,carbamoyl group, halogen atom, hydroxy group, carboxy group, loweralkoxy group and mono- or di-substituted amino group; mono- ordi-substituted amino group; mono- or di-substituted carbamoyl group;substituted or unsubstituted lower cycloalkyl group; substituted orunsubstituted lower cycloalkyl-CO—; substituted or unsubstituted lowercycloalkyl-lower alkyl group; substituted or unsubstituted phenyl group;substituted or unsubstituted phenyl-O—; substituted or unsubstitutedphenyl-CO—; substituted or unsubstituted phenyl-lower alkyl group;,substituted or unsubstituted phenyl-O-lower alkyl group; substituted orunsubstituted phenylsulfonyl group; substituted or unsubstitutedphenyl-lower alkoxy group; substituted or unsubstituted phenyl-loweralkoxycarbonyl group; substituted or unsubstituted lower cycloalkenylgroup; substituted or unsubstituted bicyclic heterocyclic group;substituted or unsubstituted monocyclic 5- or 6-membered heterocyclicgroup; substituted or unsubstituted monocyclic 5- or 6-memberedheterocyclic group-O—; substituted or unsubstituted monocyclic 5- or6-membered heterocyclic group-CO—; substituted or unsubstitutedmonocyclic 5- or 6-membered heterocyclic group-CO-lower alkyl group; andsubstituted or unsubstituted monocyclic 5- or 6-membered heterocyclicgroup-lower alkyl group; Substituents of Group B: lower alkyl group;lower alkoxy-substituted lower alkyl group; loweralkoxycarbonyl-substituted lower alkyl group; a hydroxy lower alkylgroup; a carboxy lower alkyl group; substituted or unsubstituted lowercycloalkyl group; substituted or unsubstituted lower cycloalkyl-loweralkyl group; substituted or unsubstituted phenyl group; substituted orunsubstituted phenyl-lower alkyl group; substituted or unsubstitutedbicyclic hydrocarbon group; substituted or unsubstituted monocyclic 5-or 6-membered heterocyclic group; substituted or unsubstitutedmonocyclic 5- or 6-membered heterocyclic group-lower alkyl group; andsubstituted or unsubstituted bicyclic heterocyclic group-lower alkylgroup.
 5. The method according to any one of claims 1, 2, or 3, whereinwhen the substituent selected from the substituents of Group A is amono- or di-substituted amino lower alkyl group, a mono- ordi-substituted amino group, or a mono- or di-substituted carbamoylgroup, then the substituent has one or more substituents selected fromthe substituents of Group C mentioned below; and when the substituentselected from the substituents of Group A is a substituted lowercycloalkyl group, a substituted lower cycloalkyl-CO—, a substitutedlower cycloalkyl-lower alkyl group, a substituted phenyl group, asubstituted phenyl-O—, a substituted phenyl-CO—, a substitutedphenyl-lower alkyl group, a substituted phenyl-O-lower alkyl group, asubstituted phenylsulfonyl group, a substituted phenyl-lower alkoxygroup, a substituted phenyl-lower alkoxycarbonyl group, a substitutedlower cycloalkenyl group, a substituted bicyclic heterocyclic group, asubstituted monocyclic 5- or 6-membered heterocyclic group, asubstituted monocyclic 5- or 6-membered heterocyclic group-O—, asubstituted monocyclic 5- or 6-membered heterocyclic group-CO—, asubstituted monocyclic 5- or 6-membered heterocyclic group-CO-loweralkyl group or a substituted monocyclic 5- or 6-membered heterocyclicgroup-lower alkyl group, then the substituent has one or moresubstituents selected from a halogen atom, cyano group, nitro group, oxogroup and the substituents of Group C mentioned below; and when thesubstituent selected from the substituents of Group B is a substitutedlower cycloalkyl group, a substituted lower cycloalkyl-lower alkylgroup, a substituted phenyl group, a substituted phenyl-lower alkylgroup, a substituted bicyclic hydrocarbon group, a substitutedmonocyclic 5- or 6-membered heterocyclic group, a substituted monocyclic5- or 6-membered heterocyclic group-lower alkyl group or a substitutedbicyclic heterocyclic group-lower alkyl group, then the substituent hassubstituent(s) selected from the substituents of Group C mentionedbelow; Substituents of Group C: a lower alkyl group; a hydroxy-loweralkyl group; a lower alkanoyl group; a lower cycloalkylcarbonyl group; alower alkoxy group; a lower alkoxycarbonyl group; a lower alkylsulfonylgroup; a di-lower alkyl-substituted carbamoyl group; a di-loweralkylamino-substituted lower alkanoyl group; a substituted orunsubstituted phenyl group; a substituted or unsubstituted phenyl-O—; asubstituted or unsubstituted phenyl-CO—; a substituted or unsubstitutedphenyl-lower alkanoyl group; a substituted or unsubstituted phenyl-loweralkyl group; a substituted or unsubstituted phenyl-lower alkoxy group; asubstituted or unsubstituted monocyclic 5- or 6-membered heterocyclicgroup; a substituted or unsubstituted monocyclic 5- or 6-memberedheterocyclic group-O—; a substituted or unsubstituted monocyclic 5- or6-membered heterocyclic group-CO—; and a substituted or unsubstitutedmonocyclic 5- or 6-membered heterocyclic group-substituted amino group;(in the substituents of Group C, a substituent in the substituted phenylgroup portion or the substituted monocyclic 5- or 6-memberedheterocyclic group portion is selected from a halogen atom, cyano group,nitro group, oxo group, a lower alkyl group, a lower alkoxy group, alower alkanoyl group and a lower alkoxycarbonyl group).
 6. The methodaccording to any one of claims 1, 2, or 3, wherein R² is (1) a cyclicgroup which may be substituted, where the cyclic group portion is agroup selected from the following (i) to (iv) (i) a monocyclichydrocarbon group having 3 to 7 carbon atoms, (ii) a bicyclichydrocarbon group having 9 to 11 carbon atoms, (iii) a monocyclicheterocyclic group containing 1 or 2 hetero atoms selected from nitrogenatom, oxygen atom and sulfur atom, and (iv) a bicyclic heterocyclicgroup containing 1 to 3 hetero atoms selected from nitrogen atom, oxygenatom and sulfur atom and comprising two 5- to 7-membered rings beingfused; or (2) a substituted amino group.
 7. The method according to anyone of claims 1, 2, or 3, wherein R² is (1) a cyclic group which may besubstituted, where the cyclic group portion is a group selected fromphenyl group, cyclohexyl group, cyclopentyl group, cyclobutyl group,cyclopropyl group, an indanyl group, an indenyl group, a naphthyl group,tetrahydronaphthyl, a pyrrolidinyl group, an imidazolidinyl group, apyrazolidinyl group, an oxolanyl group, a thiolanyl group, a pyrrolinylgroup, an imidazolinyl group, a pyrazolinyl group, a pyrrolyl group, animidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolylgroup, a furyl group, an oxazolyl group, an isoxazolyl group, anoxadiazolyl group, a thienyl group, a thiazolyl group, an isothiazolylgroup, a thiadiazolyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a thiomorpholinyl group, a pyridyl group, apyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a pyranylgroup, a tetrahydropyridyl group, a dihydropyridazinyl group, aperhydroazepinyl group, a perhydrothiazepinyl group, an indolinyl group,an isoindolinyl group, an indolyl group, an indazolyl group, anisoindolyl group, a benzimidazolyl group, a benzothiazolyl group, abenzoxazolyl group, a benzodioxolanyl group, a benzothienyl group, abenzofuryl group, a thienopyridyl group, a thiazolopyridyl group, apyrrolopyridyl group, a dihydropyrrolopyridyl group, a quinolyl group,an isoquinolyl group, a quinoxalinyl group, a quinazolinyl group, aphthalazinyl group, a cinnolinyl group, a chromanyl group, anisochromanyl group, a naphthyridinyl group and partially or completelysaturated cyclic groups thereof; or (2) a substituted amino group. 8.The method according to any one of claims 1, 2, or 3, wherein R² is (1)a cyclic group which may be substituted, where the cyclic group portionis a group selected from the group consisting of phenyl group,cyclohexyl group, a pyrrolidinyl group, a tetrazolyl group, a furylgroup, a thienyl group, a thiazolyl group, a piperidyl group, apiperazinyl group, a morpholinyl group, a thiomorpholinyl group, apyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinylgroup, a perhydroazepinyl group, an indolinyl group, an isoindolinylgroup, a benzothienyl group, a thienopyridyl group, a pyrrolopyridylgroup, a dihydropyrrolopyridyl group, a quinolyl group, an isoquinolylgroup, a quinoxalinyl group and partially or completely saturated cyclicgroups thereof; or (2) a substituted amino group.
 9. The methodaccording to any one of claims 1, 2, or 3, wherein R² is (1) a cyclicgroup which may be substituted, where the cyclic group portion is agroup selected from the group consisting of a pyrrolidinyl group, apiperidyl group, a piperazinyl group, a morpholinyl group, athiomorpholinyl group, a pyridyl group, a pyrimidinyl group, anindolinyl group, an isoindolinyl group, a pyrrolopyridyl group, adihydropyrrolopyridyl group and partially or completely saturated cyclicgroups thereof; or (2) a substituted amino group.
 10. The methodaccording to any one of claims 1, 2, or 3, wherein R² is (1) a cyclicgroup which may have 1 to 3 substituents which are the same or differentand selected from the substituents of Group A′ mentioned below, wherethe cyclic group portion is selected from the group consisting of apyrrolidinyl group, a piperidyl group, a piperazinyl group, amorpholinyl group, a thiomorpholinyl group, a pyridyl group, apyrimidinyl group, an indolinyl group, an isoindolinyl group, apyrrolopyridyl group, a dihydropyrrolopyridyl group and partially orcompletely saturated cyclic groups thereof; or (2) an amino groupsubstituted by 1 or 2 substituents which are the same or different andselected from the substituents of Group B′ mentioned below; Substituentsof Group A′: a halogen atom, cyano group, nitro group, oxo group,carbamoyl group, a lower alkyl group, a lower alkoxy group, a loweralkanoyl group, a lower alkoxycarbonyl group, a lower alkoxy-substitutedlower alkyl group, a mono- or di-substituted amino group, a mono- ordi-substituted carbamoyl group, a lower cycloalkyl-CO—, a substituted orunsubstituted phenyl group, a substituted or unsubstituted phenyl-loweralkyl group, a substituted or unsubstituted monocyclic 5- or 6-memberedheterocyclic group, a substituted or unsubstituted monocyclic 5- or6-membered heterocyclic group-O—, and a substituted or unsubstitutedmonocyclic 5- or 6-membered heterocyclic group-CO—; Substituents ofGroup B′: a lower alkyl group, a lower cycloalkyl group, a loweralkoxy-substituted lower alkyl group, a pyrimidinyl group, a thiazolylgroup and a thiadiazolyl group.
 11. The method according to any one ofclaims 1, 2, or 3, wherein A is —CH₂—, and R¹ is hydrogen atom.
 12. Themethod according to any one of claims 1, 2, or 3, wherein A is —CH₂—, R¹is hydrogen atom, and R² is a cyclic group which may be substituted. 13.The method according to any one of claims 1, 2, or 3, wherein A is—CH₂—, R¹ is hydrogen atom, and R² is a substituted amino group.
 14. Themethod according to any one of claims 1, 2, or 3, wherein the aliphaticnitrogen-containing 5-membered ring compound is selected from the groupconsisting of:(S)-2-cyano-1-[trans-4-(dimethylaminocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(morpholinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(N-ethyl-N-methoxyethylamino-carbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(N-ethyl-N-isopropylaminocarbonyl)-cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(N-methyl-N-butylaminocarbonyl)-cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-[(S)-2-methoxymethylpyrrolidin-1-ylcarbonyl]cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(3-carbamoylpiperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-acetylpiperazin-1-yl-carbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(2-isoindolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-[4-(3-pyridylcarbonyl)piperazin-1-ylcarbonyl]cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-{trans-4-[4-(3-thenoyl)piperazin-1-yl-carbonyl]cyclohexylamino}acetylpyrrolidine;(S)-2-cyano-1-{trans-4-[4-(4-chlorophenyl)piperazin-1-ylcarbonyl]cyclohexylamino}acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(cis-2,6-dimethylmorpholinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(5-nitro-2-isoindolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(piperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-carbamoylpiperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(1-pyrrolidinylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-cyclopropylcarbonylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-propionylpiperazin-1-yl-carbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(1-indolinylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(2,3-dihydro-1H-pyrrolo[3,4-b]pyridin-2-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-[4-(2-pyrimidinyloxy)-piperidinocarbonyl]cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-{trans-4-[4-(5-bromo-2-pyrimidinyloxy)-piperidinocarbonyl]cyclohexylamino}acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(cis-3,5-dimethyl-4-benzylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-cyclohexylcarbonylaminopiperidinocarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-{trans-4-[4-(N-phenylcarbamoyl)piperazin-1-ylcarbonyl]cyclohexylamino}acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(4-ethoxycarbonylpiperazin-1-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-[4-(2-thienyl)piperidinocarbonyl]cyclohexylamino]acetylpyrrolidine;(S)-2-cyano-1-[trans-4-(1,1-dioxoperhydro-1,4-thiazin-4-ylcarbonyl)cyclohexylamino]acetylpyrrolidine;(R)-4-cyano-3-[trans-4-(dimethylaminocarbonyl)cyclohexylamino]acetylthiazolidine;(R)-4-cyano-3-[trans-4-(2-isoindolinylcarbonyl)cyclohexylamino]acetylthiazolidine;(R)-4-cyano-3-[trans-4-(morpholinocarbonyl)cyclohexylamino]acetylthiazolidine;and(R)-4-cyano-3-[trans-4-(pyrrolidinylcarbonyl)cyclohexylamino]acetylthiazolidine;or a pharmaceutically acceptable salt thereof.